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First-principles molecular dynamics combined with the approach-to-equilibrium molecular dynamics methodology is employed to calculate the thermal conductivity of non-stoichiometric amorphous SiN. This is achieved by implementing thermal transients in five distinct models of different sizes along the direction of the heat transport. Such models have identical structural features and are representative of the same material, thereby allowing for a reliable analysis of thermal conductivity trends as a function of the relevant cell dimension. In line with the known physical law of heat propagation at short scale, the thermal conductivity increases in size with the direction of heat transport. The observed behavior is rationalized accounting for previous results on crystalline and amorphous materials, thus providing a unified description holding for a large class of materials and spanning a wide range of heat propagation lengths. [ABSTRACT FROM AUTHOR]

The formation of biomolecular condensates in vivo is increasingly recognized to underlie a multitude of crucial cellular functions. Furthermore, the evolution of highly dynamic protein condensates into progressively less reversible assemblies is thought to be involved in a variety of disorders, from cancer over neurodegeneration to rare genetic disorders. There is an increasing need for efficient experimental methods to characterize the thermodynamics of condensate formation and that can be used in screening campaigns to identify and rationally design condensate modifying compounds. Theoretical advances in the field are also identifying the key parameters that need to be measured in order to obtain a comprehensive understanding of the underlying interactions and driving forces. Here, we review recent progress in the development of efficient and quantitative experimental methods to study the driving forces behind and the temporal evolution of biomolecular condensates. [ABSTRACT FROM AUTHOR]

BACKGROUND: LncRNA-TNFRSF13C, an important factor in B cell development and function, is expressed in periodontal tissues of patients with periodontitis, but the specific mechanism is still unclear. OBJECTIVE: To investigate the mechanism of lncRNA-TNFRSF13C regulating miR-1246 on hypoxia-inducible factor 1α in periodontal cells. METHODS: Human periodontal ligament cells (hPDLCs) were treated with lipopolysaccharide and divided into group A (hPDLCs cell lines without transfection), group B (hPDLCs cell lines transfected with TNFRSF13C NC-siRNA), group C (hPDLCs cell lines transfected with TNFRSF13C-siRNA), group D (hPDLCs cell line transfected with miR-1246 mimics), group E (hPDLCs cell line transfected with miR-1246 siRNA), group F (hPDLCs cell line transfected with TNFRSF13C- siRNA+miR-1246 mimics), and group G (hPDLCs cell line transfected with TNFRSF13C-siRNA+miR-1246 siRNA). The relative expression of lncRNA-TNFRSF13C and miR-1246 in each group was detected by qRT-PCR. Cell counting kit-8 assay was used to detect cell viability. Apoptosis was detected by flow cytometry. Expression of hypoxia-inducible factor 1α and vascular endothelial growth factor proteins was detected by western blot. The correlation between lncRNA- TNFRSF13C and miR-1246 was analyzed by Pearson, and the targeting relationship was analyzed by dual-luciferase reporter assay. RESULTS AND CONCLUSION: There was no significant difference in human periodontal ligament cell activity, apoptosis rate and protein indexes between groups A and B (P >0.05). Compared with group B, hPDLCS cell activity in group C was increased, and apoptosis rate and the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor proteins were decreased (P < 0.05). Compared with group C, hPDLCS cell activity in group D was decreased, and apoptosis rate and the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor proteins were increased (P < 0.05). Compared with group D, the cell activity of group E was increased (P < 0.05). The cell activity in group F was lower than that in group E, and the apoptosis rate was reduced in both groups E and F (P < 0.05). Compared with group F, the cell activity of group G was increased, and the apoptosis rate and the expression of hypoxia- inducible factor 1α and vascular endothelial growth factor were decreased (P < 0.05). LncRNA-TNFRSF13C was positively correlated with miR-1246 (P < 0.05). Compared with the TNFRSF13C-siRNA group, the fluorescence activity of miR-1246-wt in the TNFRSF13C-NC group was reduced (P > 0.05); compared with the miR-1246-NC group, the fluorescence activities of hypoxia-inducible factor 1α-wt and vascular endothelial growth factor-wt in the miR-1246 mimics group were increased (P < 0.05). To conclude, down-regulation of lncRNA-TNFRSF13C can promote the activity of periodontal cells treated with lipopolysaccharide, reduce apoptosis, and inhibit hypoxia-inducible factor 1α and vascular endothelial growth factor. The mechanism is related to the regulation of miR-1246 activity. [ABSTRACT FROM AUTHOR]

Background: Testosterone deficiency (TD) occurs most frequently in older men and can cause many health problems. Testosterone replacement therapy (TRT) is widely used to treat TD, but this regimen can lead to a series of side effects. Stem cell therapy has been wildly studied in vitro. However, due to the multidirectional differentiation potential and heterogeneity of stem cells, it is difficult to achieve the good efficiency and reproducibility in basic research and clinical applications. This study aims to identify a new strategy for the treatment of TD. Methods: Bone marrow-derived mesenchymal stromal cells (BMSCs) were enucleated by Ficoll density gradient centrifugation. The organelles and cellular functions of enucleated BMSCs were analyzed by immunofluorescence staining and flow cytometry. Extracellular vesicles (EVs) were isolated by ultracentrifugation and characterized. For the animal studies, enucleated BMSCs were labelled with Mitotracker and injected into ethane dimethanesulfone (EDS)-treated rats. Testosterone production and spermatogenesis were detected at different time points through various tests. To determine the mechanism of efferocytosis, we analysed the number of macrophages by immunofluorescence staining and quantitative real-time polymerase chain reaction (qRT-PCR). Results: The injection of enucleated BMSCs (Cargocytes) into the testes of EDS-treated rats restored the levels of serum testosterone, increased the number of Leydig cells (LCs), and improved spermatogenesis. We found that enucleated BMSCs underwent apoptosis earlier than BMSCs did. Subsequently, testicular interstitial macrophages phagocytosed apoptotic enucleated BMSCs through efferocytosis. Efferocytosis promoted macrophage polarization from the M1 to the M2 phenotype, reduced the expression of proinflammatory cytokines, and decreased the levels of inflammation and oxidative stress. Conclusions: In summary, this study pioneered the application of stromal cell enucleation technology to repair tissue damage in the reproductive system, explored the potential of cell burial in the treatment of reproductive system diseases and provided a new approach for the clinical treatment of male infertility. [ABSTRACT FROM AUTHOR]

Tissue maintenance is underpinned by resident stem cells whose activity is modulated by microenvironmental cues. Using Drosophila as a simple model to identify regulators of stem cell behaviour and survival in vivo, we have identified novel connections between the conserved transmembrane proteoglycan Syndecan, nuclear properties and stem cell function. In the Drosophila midgut, Syndecan depletion in intestinal stem cells results in their loss from the tissue, impairing tissue renewal. At the cellular level, Syndecan depletion alters cell and nuclear shape, and causes nuclear lamina invaginations and DNA damage. In a second tissue, the developing Drosophila brain, live imaging revealed that Syndecan depletion in neural stem cells results in nuclear envelope remodelling defects which arise upon cell division. Our findings reveal a new role for Syndecan in the maintenance of nuclear properties in diverse stem cell types. Author summary: Most tissues are built and maintained by stem cells that divide to produce correct cell types in response to environmental cues. In high turnover tissues, such as the intestine, a fundamental question is how stem cells themselves are maintained over time in the face of physical and chemical damage. Here, we show that the evolutionary conserved adhesion protein Syndecan contributes to intestinal stem cell survival by promoting the maintenance of nuclear properties in Drosophila. We show that this novel Syndecan-nucleus connection is not unique to intestinal stem cells and operates in neural stem cells of the developing brain too, affecting how fast these cells can divide. In the intestine however, due to higher sensitivity to Syndecan loss, stem cells develop DNA damage and fail to produce new intestinal cells, compromising cell production. Overall, our work highlights a novel stem cell survival mechanism that may be especially relevant in tissues with high mechanical perturbations. [ABSTRACT FROM AUTHOR]

The Shaker/Kv1 subfamily of voltage-gated potassium (K+) channels is essential for modulating membrane excitability. Their loss results in prolonged depolarization and excessive calcium influx. These channels have also been implicated in a variety of other cellular processes, but the underlying mechanisms remain poorly understood. Through comprehensive screening of K+ channel mutants in C. elegans, we discovered that shk-1 mutants are highly susceptible to bacterial pathogen infection and oxidative stress. This vulnerability is associated with reduced glycogen levels and substantial mitochondrial dysfunction, including decreased ATP production and dysregulated mitochondrial membrane potential under stress conditions. SHK-1 is predominantly expressed and functions in body wall muscle to maintain glycogen storage and mitochondrial homeostasis. RNA-sequencing data reveal that shk-1 mutants have decreased expression of a set of cation-transporting ATPases (CATP), which are crucial for maintaining electrochemical gradients. Intriguingly, overexpressing catp-3, but not other catp genes, restores the depolarization of mitochondrial membrane potential under stress and enhances stress tolerance in shk-1 mutants. This finding suggests that increased catp-3 levels may help restore electrochemical gradients disrupted by shk-1 deficiency, thereby rescuing the phenotypes observed in shk-1 mutants. Overall, our findings highlight a critical role for SHK-1 in maintaining stress tolerance by regulating glycogen storage, mitochondrial homeostasis, and gene expression. They also provide insights into how Shaker/Kv1 channels participate in a broad range of cellular processes. Author summary: Exposure to environmental stimuli, such as bacterial pathogens, increases the production of reactive oxygen species (ROS), leading to oxidative stress and widespread cellular damage. Cells employ various defense mechanisms to counteract ROS-induced damages and maintain cellular homeostasis. In this study, we found that the Shaker/Kv1 channel SHK-1, typically known for its regulation of membrane excitability, also helps protect C. elegans against bacterial infections and oxidative stress. Animals lacking shk-1 are highly sensitive to pathogens and prooxidant exposure, and show defects in gene expression, glycogen storage, and mitochondrial function. Notably, shk-1 mutants have reduced expression of catp-3, encoding one of cation-transporting ATPases that are critical for maintaining ion balance. Restoring catp-3 expression rescues the defects observed in shk-1-deficient animals, suggesting that the loss of SHK-1 likely disturbs ion homeostasis, which can be mitigated by increased levels of catp-3. These findings offer a new perspective on the fundamental mechanism by which SHK-1 regulates diverse cellular functions. Moreover, our observations may have implications for how Kv1.3 is involved in various physiological processes in mammals. [ABSTRACT FROM AUTHOR]

The minor spliceosome catalyzes excision of U12-dependent introns from precursors of eukaryotic messenger RNAs (pre-mRNAs). This process is critical for many cellular functions, but the underlying molecular mechanisms remain elusive. Here, we report a cryoelectron microscopy (cryo-EM) reconstruction of the 13-subunit human U11 small nuclear ribonucleoprotein particle (snRNP) complex in apo and substrate-bound forms, revealing the architecture of the U11 small nuclear RNA (snRNA), five minor spliceosome-specific factors, and the mechanism of the U12-type 5′ splice site (5′SS) recognition. SNRNP25 and SNRNP35 specifically recognize U11 snRNA, while PDCD7 bridges SNRNP25 and SNRNP48, located at the distal ends of the particle. SNRNP48 and ZMAT5 are positioned near the 5′ end of U11 snRNA and stabilize binding of the incoming 5′SS. Recognition of the U12-type 5′SS is achieved through base-pairing to the 5′ end of the U11 snRNA and unexpected, non-canonical base-triple interactions with the U11 snRNA stem-loop 3. Our structures provide mechanistic insights into U12-dependent intron recognition and the evolution of the splicing machinery. [Display omitted] • Cryo-EM reveals the architecture of the minor spliceosomal U11 snRNP • Unique U11 snRNA structure allows recruitment of minor spliceosome-specific factors • U11 snRNP is very distinct from the major spliceosomal U1 snRNP counterpart • U12-type 5′SS recognition involves base-pairing and non-canonical interactions Zhao et al. present two cryo-EM structures of apo and substrate-bound U11 snRNP complexes, elucidating their architecture and the mechanism of the U12-type 5′ splice site recognition. The unique structure of the U11 snRNA is incompatible with the binding of U1 snRNP-specific proteins, providing a structural basis for specific recognition. [ABSTRACT FROM AUTHOR]

Liquid storage is the primary preservation method in the swine breeding industry because of its advantages over cryopreservation. Calcium (Ca2+), a key regulator of cell physiology, plays a crucial role during liquid preservation. Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPases (SERCA) belong to a family of P-type ATPases that regulate Ca2+ homeostasis within cells and have been previously described to play a function in the sperm of various mammalian species. Herein, we hypothesized that SERCA2 is present in pig sperm and is involved in the resilience of this cell to liquid preservation at 17 °C. For this purpose, sperm were incubated with different concentrations of thapsigargin (Thg; 0, 5, 25, and 50 µM) and stored at 17 °C for ten days. The presence and localization of SERCA2 were evaluated using immunoblotting and immunofluorescence, respectively. On days 0, 4, and 10, sperm motility was assessed using a computer-assisted sperm analysis (CASA) system, and sperm viability, membrane lipid disorder, acrosome integrity, mitochondrial membrane potential (MMP), and intracellular levels of Ca2+, superoxides and total reactive oxygen species (ROS) were evaluated by flow cytometry. We localized SERCA2 in the acrosome and midpiece of pig sperm. Furthermore, inhibition of SERCA with Thg resulted in reduced sperm viability and membrane stability, and increased MMP, and Ca2+ and ROS levels. In conclusion, the activity of SERCA prevents the accumulation of intracellular Ca2+ in sperm, which is detrimental to sperm quality and function during liquid storage at 17 °C. We thus suggest that the function of SERCA is crucial for the preservation of pig semen. [ABSTRACT FROM AUTHOR]

Cell type-specific actions of disease genes add a significant layer of complexity to the genetic architecture underlying diseases, obscuring our understanding of disease mechanisms. Single-cell omics have revealed the functional roles of genes at the cellular level, identifying cell types critical for disease progression. Often, a gene impact on disease through its altered network within specific cell types, rather than mere changes in expression levels. To explore the cell type-specific roles of disease genes, we developed HCNetlas (human cell network atlas), a resource cataloging cell type-specific gene networks (CGNs) for various healthy tissue cells. We also devised 3 network analysis methods to investigate cell type-specific functions of disease genes. These methods involve comparing HCNetlas CGNs with those derived from disease-affected tissue samples. These methods find that systemic lupus erythematosus genes predominantly function in myeloid cells, and Alzheimer's disease genes mainly play roles in inhibitory and excitatory neurons. Additionally, they suggest that many lung cancer-related genes may exert their roles in immune cells. These findings suggest that HCNetlas has the potential to link disease-associated genes to cell types of action, facilitating development of cell type-resolved diagnostics and therapeutic strategies for complex human diseases. Alterations of gene regulatory networks in specific cell types can cause disease. These authors create HCNetlas (Human Cell Network Atlas), a compilation of cell-type-specific gene networks across a range of healthy tissues that can be used to uncover associations between disease genes and specific cell types. [ABSTRACT FROM AUTHOR]

Sensorineural hearing loss (SNHL) is the most prevalent form of permanent hearing impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue of the JCI, Lee et al. reveal a link between mutations in ATF6 and SNHL in patients with achromatopsia. The study also shows that Atf6-deficient (Atf6-/-) mice exhibit disorganized stereocilia and age-related loss of outer hair cells. Additionally, the researchers show that Atf6 is critical for cochlear hair cell function. Mice lacking Atf6 expression experienced ER stress, which ultimately led to SNHL. Collectively, these findings enhance our understanding of the emerging role of protein homeostasis and ER stress in the pathogenesis of SNHL. [ABSTRACT FROM AUTHOR]

AbstractA growing body of research on extracellular vesicles (EVs) in cancer has revealed their novel and crucial activities in the progression of tumors while also paving the way for potential therapeutic interventions. It is now known that EVs are natural delivery vehicles for particular payloads of source cells, enabling them to influence diverse functions of cells both in healthy and malignant cells. In this review, we comprehensively summarize mechanistic insights into sEV roles in RB, the most frequent intraocular malignancy that affects the retina of young children. We also explore the therapeutic potential of sEVs as an emerging area as biomarkers and vehicles for targeted therapy. Additionally, we address the potential challenges and limitations of translating sEVs-based technologies into clinical practice. [ABSTRACT FROM AUTHOR]

C4 plants have C4 photosynthetic cycle, a CO2-concentrating pump that functions across mesophyll (M) and bundle sheath (BS) cells. M chloroplasts aggregate toward BS cells in response to environmental stress, which would contribute to adjustment in C4 photosynthetic cycle. However, it remains unclear whether M chloroplast movement is an intercellular response mediated by BS cells. One major challenge to resolve this is the difficulty in observing chloroplast movement due to scattering and absorption of observation light in live-leaf tissues. We established a live leaf-section imaging technique that enables the long-term observation of sections of chemically unfixed leaf blades, with which we quantitatively analyzed M chloroplast movements. Another challenge in clarifying the contribution of BS cells to M chloroplast movement is the selective ablation of BS cells without impairing M cell function. To investigate the necessity of BS cells for M chloroplast movement, we developed a method to remove BS cells only based on differences in shape between M and BS cells. We also found that chloroplasts in M cells without adjacent BS cell contents did not show typical aggregative movement. This indicates that the M chloroplast aggregative movement occurs during communication with BS cells. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG) of the hippocampus has been implicated in the regulation of stress responses, and in the pathophysiology and treatment of depression. This review discusses the cellular changes caused by chronic stress and the cellular role of the DG in stress-induced behavioral changes and its antidepressant-like effects. Regarding adult-born neurogenic processes in the DG, chronic stress, such as repeated social defeat, suppresses cell proliferation during and immediately after stress; however, this effect is transient. The subsequent differentiation and survival processes are differentially regulated depending on the timing and sensitivity of stress. The activation of young adult-born neurons during stress contributes to stress resilience, while the transient increase in the survival of adult-born neurons after the cessation of stress seems to promote stress susceptibility. In mature granule neurons, the predominant cells in the DG, synaptic plasticity is suppressed by chronic stress. However, a group of mature granule neurons is activated by chronic stress. Chronic antidepressant treatment can transform mature granule neurons to a phenotype resembling that of immature neurons, characterized as "dematuration". Adult-born neurons suppress the activation of mature granule neurons during stress, indicating that local neural interactions within the DG are important for the stress response. Elucidating the stress-associated context- and timing-dependent cellular changes and functions in the DG will provide insights into stress-related psychiatric diseases. • Hippocampal DG regulates stress responses and is involved in the pathophysiology and treatment of depression. • Chronic stress differentially regulates adult neurogenic processes in the DG depending on the timing and sensitivity of stress. • The activation of young adult-born neurons during stress may contribute to stress resilience. • Chronic antidepressant treatment transforms the phenotype of mature GCs in the DG into immature-like ones. [ABSTRACT FROM AUTHOR]

The rapid development of nanotechnology has resulted in the widespread use of nanoparticles (NPs) in various sectors due to their unique properties and diverse applications. However, the increased exposure of humans to NPs raises concerns about their potential negative impact on human health and the environment. The pathways through which NPs exert adverse effects, including inflammation and oxidative stress, are primarily influenced by their size, shape, surface charge, and chemistry, underscoring the critical need to comprehend and alleviate their potential detrimental impacts. In this context, the natural flavonoid quercetin is a promising candidate for counteracting the toxicity induced by NPs due to its anti-inflammatory and antioxidant properties. This review provides an overview of the existing literature on quercetin's protective effects against NPs-induced toxicity, highlighting its therapeutic benefits and mechanisms of action, focusing on its ability to alleviate oxidative stress, inflammation, and cellular damage caused by various types of NPs. Insights from both in vitro and in vivo studies demonstrate the effectiveness of quercetin in preserving cellular function, modulating apoptotic pathways, and maintaining tissue integrity in the presence of NPs. The potential of quercetin as a natural therapeutic agent against NPs-induced toxicity provides valuable insights for safer use of NPs in various daily applications. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. Methods: We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. Results: Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. Conclusion: Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function. [ABSTRACT FROM AUTHOR]

Filopodia are increasingly recognized as essential structures in various cellular processes such as embryogenesis, neurogenesis, and cardiogenesis, where they play a crucial role in signaling and coordinating morphogenetic events. Viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), induce filopodia growth by reprogramming cell signaling pathways, thereby promoting the efficient spread of the virus. Theoretical modeling offers fresh mechanistic insights into the dynamic functions of filopodia, elucidating processes such as retraction, pushing, and rotation. The use of optical tweezers and molecular tension sensors enables a comprehensive mechanical examination, providing detailed insights into the forces acting along filopodia. Filopodia, widely distributed on cell surfaces, are distinguished by their dynamic extensions, playing pivotal roles in a myriad of biological processes. Their functions span from mechanosensing and guidance to cell–cell communication during cellular organization in the early embryo. Filopodia have significant roles in pathogenic processes, such as cancer invasion and viral dissemination. Molecular mapping of the filopodome has revealed generic components essential for filopodia functions. In parallel, recent insights into biophysical mechanisms governing filopodia dynamics have provided the foundation for broader investigations of filopodia's biological functions. We highlight recent discoveries of engagement of filopodia in various stages of development and pathogenesis and present an overview of intricate molecular and physical features of these cellular structures across a spectrum of cellular activities. [ABSTRACT FROM AUTHOR]

Within the scope of this investigation, educational instruments grounded on materialist ontology were employed to undertake a semantic analysis of the concepts of cell and the mechanisms of living organisms as they appear in biology and natural science textbooks. Drawing upon the ontological categories applied to distinct biological system levels, our findings demonstrate that the dominant approach for introducing the concept of cell and living organisms is via a holistic approach. However, prevalent inaccuracies relate to the presentation of tissue or organ properties, which neglect to reference the types of cells and their interactions responsible for emergent properties at this level. Our findings suggest that the use of a holistic approach to teach the functioning of living beings, may partially account for the difficulties when transitioning between levels of reality to construct explanations by students in this field of study. Our work provides tools to transition towards a biology education with a systemic approach to the content of cells and living organisms. [ABSTRACT FROM AUTHOR]

Microplastics and nanoplastics (MNPs) are being recognized as new cardiovascular risk factors, impacting vascular cell functions and exacerbating atherosclerosis through diverse mechanisms. However, the varied concentrations of MNPs detected in major cardiovascular tissues highlight the urgent need for standardized research methodologies to better understand their impact and inform future health guidelines. [ABSTRACT FROM AUTHOR]

Introduction Acute pain in cancer is an important but often overlooked feature of many patients' oncological journey. Cancer-related pain is associated commonly with more persistent pain states caused by both the disease and its treatment, but there are numerous causes of acute pain which can develop in patients with cancer. This pain is frequently severe, can be challenging to manage and its suboptimal control can directly impact on oncological outcomes. This narrative review provides an overview of several causes of acute pain in patients with cancer and management approaches. Methods A focused literature review was conducted to encompass the search terms 'acute pain', 'oncology' and 'cancer' in adult and paediatric populations. Results Acute pain is common in patients with cancer with a number of pain generators identified. Broadly, these are disease- and treatment-related but commonality in pain mechanisms and features are present. Importantly, these pain states do not occur in isolation; a patient may experience multiple acute pain episodes during their oncology journey. Discussion As the oncological treatment landscape shifts and increasing numbers of novel treatments are employed, the number of causes of acute pain in patients with cancer rises. This pain is often managed by non-pain specialists and suboptimal control has a variety of deleterious effects. It is important that awareness of acute pain in the oncological population is increased and treatment approaches, which adopt a biopsychosocial structure, are optimised. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and current treatments are limited by high toxicity and low survival rates, highlighting the need for new therapeutic approaches. Natural killer (NK) cells can identify and eliminate cancer cells without prior antigen exposure. Radiotherapy directly targets tumors and increases activating ligands on tumor cells, promoting NK cell interactions. Cetuximab, an EGFR-targeting antibody, enhances NK cell cytotoxicity. Additionally, anti-PD-1 antibodies may further boost NK cell function by blocking inhibitory signals. The study aimed to enhance HNSCC treatment efficacy by combining radiotherapy and targeted therapy with expanded NK cells. Methods: NK cells were isolated, activated, and expanded from healthy donors. The FaDu and SCC-47 cell lines were inoculated into NOD/SCID mice. The mice were treated with PD-1 inhibitors, cetuximab, and radiation, followed by intravenous injection of NK cells. Results: Radiation increased ligands that regulate NK cell sensitivity. The combination of cetuximab, radiotherapy, and expanded NK cells significantly suppressed cancer progression and improved survival rates. However, adding anti-PD-1 antibodies did not further enhance outcomes. Conclusion: This study suggests that a multimodal approach combining cetuximab, radiotherapy, and NK cells can significantly improve HNSCC therapy efficacy, offering a novel and promising treatment strategy. [ABSTRACT FROM AUTHOR]

Background: Buserelin has been used to treat central precocious puberty (CPP). However, it could potentially result in immune dysregulation to undermine patients' health. Therefore, it is necessary to elucidate the effects of buserelin on immune cells. Here we explored buserelin-induced impacts on the differentiation and function of macrophage-colony-stimulating factor-producing T helper (ThGM) cells to uncover the immunoregulatory role of buserelin. Methods: Rat CPP was induced by danazol injection followed by buserelin treatment. The frequencies of ThGM cells in the spleen and lymph nodes were evaluated by flow cytometry. ThGM cell generation and function were analyzed in cell culture assays. Cell signaling was measured by Immunoblotting. Results: Buserelin increased the frequencies of splenic and lymph node ThGM cells. Buserelin promoted the in vitro differentiation and proliferation of ThGM cells. Buserelin-treated ThGM cells showed stronger supportive effects on other effector T helper cells. Buserelin induced the activation of the nuclear factor of activated T cells and extracellular signal-regulated kinase 1/2 in ThGM cells. Conclusion: Buserelin enhances the differentiation and function of pro-inflammatory ThGM cells, thus increasing the risk of autoimmune or inflammatory disorders. Therefore, it is necessary to monitor ThGM cells in buserelin-treated children to prevent latent immune dysregulation. [ABSTRACT FROM AUTHOR]

Small, or short, open reading frames (smORFs) of less than 100 codons exist in the hundreds of thousands in every transcriptome but until recently have been discarded as nonfunctional. Ribosomal profiling reveals translation of at least hundreds of smORFs, often at low levels undetected by proteomics. This translation can produce no biologically detectable peptide but still have a cis effect on the synthesis or stability of the encoding RNA. Robustly translated smORF peptides often regulate canonical proteins associated with cellular membranes and organelles. These regulatory inputs can modulate deeply conserved cellular and physiological functions. The functional and translational profiles of smORFs suggest an evolutionary process producing new peptides from noncoding sequences. Hundreds of thousands of small open reading frames (smORFs) of less than 100 codons exist in every genome, especially in long noncoding RNAs (lncRNAs) and in the 5′ leaders of mRNAs. smORFs are often discarded as nonfunctional, but ribosomal profiling (RiboSeq) reveals that thousands are translated, while characterised smORF functions have risen from anecdotal to identifiable trends: smORFs can either have a cis-noncoding regulatory function (involving low translation of nonfunctional peptides) or full coding function mediated by robustly translated peptides, often having cellular and physiological roles as membrane-associated regulators of canonical proteins. The evolutionary context reveals that many smORFs represent new genes emerging de novo from noncoding sequences. We suggest a mechanism for this process, where cis-noncoding smORF functions provide niches for the subsequent evolution of full peptide functions. [ABSTRACT FROM AUTHOR]

Autophagy is a crucial immune defense mechanism that controls the survival and pathogenesis of M. tb by maintaining cell physiology during stress and pathogen attack. The E3-Ub ligases (PRKN, SMURF1, and NEDD4) and autophagy receptors (SQSTM1, TAX1BP1, CALCOCO2, OPTN, and NBR1) play key roles in this process. Galectins (LGALSs), which bind to sugars and are involved in identifying damaged cell membranes caused by intracellular pathogens such as M. tb, are essential. These include LGALS3, LGALS8, and LGALS9, which respond to endomembrane damage and regulate endomembrane damage caused by toxic chemicals, protein aggregates, and intracellular pathogens, including M. tb. They also activate selective autophagy and de novo endolysosome biogenesis. LGALS3, LGALS9, and LGALS8 interact with various components to activate autophagy and repair damage, while CGAS-STING1 plays a critical role in providing immunity against M. tb by activating selective autophagy and producing type I IFNs with antimycobacterial functions. STING1 activates cGAMP-dependent autophagy which provides immunity against various pathogens. Additionally, cytoplasmic surveillance pathways activated by ds-DNA, such as inflammasomes mediated by NLRP3 and AIM2 complexes, control M. tb. Modulation of E3-Ub ligases with small regulatory molecules of LGALSs and TRIM proteins could be a novel host-based therapeutic approach for controlling TB. [ABSTRACT FROM AUTHOR]

Nanoplastics (NPs), defined as plastic particles with dimensions less than 100 nm, have emerged as a persistent environmental contaminant with potential risk to both environment and human health. Nanoplastics might translocate across biological barriers and accumulate in vital organs, leading to inflammatory responses, oxidative stress, and genotoxicity, already reported in several organisms. Disruptions to cellular functions, hormonal balance, and immune responses were also linked to NPs exposure in in vitro assays. Further, NPs have been found to adsorb other pollutants, such as persistent organic pollutants (POPs), and leach additives potentially amplifying their advere impacts, increasing the threat to organisms greater than NPs alone. However, NPs toxic effects remain largely unexplored, requiring further research to elucidate potential risks to human health, especially their accumulation, degradation, migration, interactions with the biological systems and long-term consequences of chronic exposure to these compounds. This review provides an overview of the current state-of-art regarding NPs interactions with environmental pollutants and with biological mechanisms and toxicity within cells. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) has been highlighted as an important factor in cardiovascular system. As a signaling molecule in the cardiovascular system, NO can relax blood vessels, lower blood pressure, and prevent platelet aggregation. Mitochondria serve as a central hub for cellular metabolism and intracellular signaling, and their dysfunction can lead to a variety of diseases. Accumulating evidence suggests that NO can act as a regulator of mitochondria, affecting mitochondrial function and cellular activity, which in turn mediates the onset and progression of disease. However, there is a lack of comprehensive understanding of how NO regulates mitochondrial function in the cardiovascular system. This review aims to summarize the regulation of mitochondrial function by nitric oxide in cardiovascular related diseases, as well as the multifaceted and complex roles of NO in the cardiovascular system. Understanding the mechanism of NO mediated mitochondrial function can provide new insights for the prevention and treatment of cardiovascular diseases. • Nitric oxide(NO) has a protective effect on the cardiovascular system. • NO can serve as a regulatory factor for mitochondria. • The potential therapeutic effects of NO targeting mitochondria in the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

MiRNAs have been identified as participants in leukemogenesis by controlling several cellular functions, such as differentiation, proliferation, and apoptosis. Their role in myelodysplastic neoplasms (MDS) pathogenesis is researched due to implementations in early identification, classification, and therapeutical options. IPSS-R, being the most widely used MDS classification, underestimates early biological events that can alter the disease's prognosis. The purpose of this study is to determine whether miRNA levels are aligned to MDS risk stratification groups and can therefore be used as diagnostic biomarkers. To evaluate miRNAs as possible biomarkers, we measured the levels of miR-181a-2-3p, miR-124-3p, miR-550a-3p, miR-155-5p, miR-151a-3p, and miR-125b-5p by a quantitative real-time PCR in bone marrow samples of 41 MDS patients. In conclusion, in myeloid malignancies, genomic characteristics may provide a wider apprehension of its clinical course and prognosis. MiRNAs constitute a possible diagnostic biomarker and therapeutic target, allowing intermediate-risk patients that express high levels of specific miRNAs to be re-classified and receive more advanced therapeutic agents. In our study, an association between high levels of miRNAs and worsening outcomes is established, supporting the need for further incorporation of molecular data into currently used classification systems. [ABSTRACT FROM AUTHOR]

The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial transcriptomics have revealed the spatial heterogeneity of immune cell distribution and function within organs such as the liver, kidney, intestine, and lung. In addition, these technologies visualize nutrient and oxygen environments across tissues. Recent spatial analyses have suggested that a functional immune niche is determined by interactions between immune and non-immune cells in an appropriate nutrient and oxygen environment. Understanding the spatial communication between immune cells, environment, and surrounding non-immune cells is crucial for developing strategies to control immune responses and effectively manage inflammatory diseases. [ABSTRACT FROM AUTHOR]

Cancer is still one of the most important diseases that have a high mortality rate around the world. The management of cancer involves many procedures, which include surgery, radiotherapy, and chemotherapy. Drug resistance in cancer chemotherapy is considered one of the most important problems in clinical oncology. A good understanding of the tumorigenesis process and the mechanisms of developing chemotherapy resistance in cancer cells will help achieve significant advances in cancer treatment protocols. In recent years, there has been an increasing interest in long noncoding RNAs (lncRNAs). LncRNAs are no longer just a transcriptional noise, and many investigations proved their possible roles in regulating mandatory cellular functions. A lot of newly published studies confirmed the implication of lncRNAs in the tumor formation process and the multiple drug resistance in cancer chemotherapy. The main aim of this review is to focus on the lncRNAs' functions in the cell, their possible roles in the tumor formation process, and their roles in the development of chemotherapy resistance in different cancer cells. [ABSTRACT FROM AUTHOR]

• SCZ astrocytes express lower levels of NLRP3-ASC corresponding to similar expression patterns in postmortem brain samples. • Higher activity of Caspase-1 upon inflammasome stimulation relative to CTRL in iPSC-astrocytes. • Skewed Th1 and Th17 lymphocyte activation capacity by SCZ astrocytes upon specific NLRP3 inflammasome activation. • Decreased resting basal glycolysis and a cell-intrinsic inability in regulating it in SCZ astroglia. Mounting evidence indicates the involvement of neuroinflammation in the development of schizophrenia (SCZ), but the potential role of astroglia in this phenomenon remains poorly understood. We assessed the molecular and functional consequences of inflammasome activation using induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Screening protein levels in astrocytes at baseline identified lower expression of the NLRP3-ASC complex in SCZ, but increased Caspase-1 activity upon specific NLRP3 stimulation compared to CTRL. Using transcriptional profiling, we found corresponding downregulations of NLRP3 and ASC/PYCARD in both iPSC-derived astrocytes, and in a large (n = 429) brain postmortem case-control sample. Functional analyses following NLRP3 activation revealed an inflammatory phenotype characterized by elevated production of IL-1β/IL-18 and skewed priming of helper T lymphocytes (Th1/Th17) by SCZ astrocytes. This phenotype was rescued by specific inhibition of NLRP3 activation, demonstrating its dependence on the NLRP3 inflammasome. Taken together, SCZ iPSC-astrocytes display unique, NLRP3-dependent inflammatory characteristics that are manifested via various cellular functions, as well as via dysregulated innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

• Divergent selection on feather pecking resulted in distinct lines characterized by high (HFP) and low feather pecking (LFP). • HFP hens showed lower numbers of CD4+ cells, CD4+ CD25high cells, and B cells compared to LFP hens. • HFP hens exhibited a stronger proliferation of T cells when stimulated with ConA. • HFP hens showed a weaker response in T cell-dependent B cell proliferation when stimulated with PWM. • Data indicate an effect of the divergent selection on feather pecking on immune cell numbers and function. • Data suggests alterations in T-cell regulation in HFP hens. Feather pecking (FP) is a serious behavioral disorder in laying hens, leading to feather damage, skin lesions, and often resulting in cannibalism. The mechanisms underlying FP are not clear yet, but recently the role of the immune system as a cause has been discussed. In humans, the interrelation between personality traits and the immune system is well-documented, with impulsivity and hyperactivity linked to distinct alterations in blood immune cell numbers and to elevated levels of pro-inflammatory cytokines. Similarly, FP in hens is associated with impulsivity and hyperactivity, suggesting a possible connection between FP and immune cell alterations. In this study numbers of leukocyte subsets in blood, spleen and cecal tonsils, along with mitogen-induced lymphocyte proliferative response and antibody concentrations across hens selectively bred for high (HFP) and low (LFP) feather pecking behavior were analyzed. Results showed that divergent selection altered FP behavior, with HFP hens showing about 10 times more pecking behavior than hens of the LFP line. HFP hens had lower numbers of T helper cells, CD4+ CD25high as well as B cells compared to LFP hens. Furthermore, HFP hens demonstrated a stronger proliferation of T cells when stimulated with ConA, while showed a weaker response in T cell-dependent B cell proliferation when stimulated with PWM, compared to LFP hens. Antibody plasma concentrations were similar between both lines. These findings highlight substantial immunological differences between HFP and LFP hens, especially in T cell immunity, and support the hypothesis that FP may be an immune-related behavioral response. [ABSTRACT FROM AUTHOR]

Background: Tumor-derived small extracellular vesicles (sEVs) play an essential role in reprogramming the tumor microenvironment. Metabolic reprogramming is an essential prerequisite for M2 polarization of tumor-associated macrophages (TAMs). This M2 phenotype is closely related to the immune dysfunction of CD8+ T cells and subsequent tumor progression. This study evaluates the role of laryngeal squamous cell carcinoma cell-derived small extracellular vesicles (LSCC-sEVs) in M2 polarization of TAMs and CD8+ T cell dysfunction, and delineates the underlying mechanisms. Methods: Human leukemia monocyte cell line (THP-1) was induced to differentiate into M0 macrophages using phorbol 12-myristate 13-acetate. M0 macrophages were incubated with sEVs derived from LSCC cells TU212. CD8+T cells, extracted from peripheral blood mononuclear cells of healthy volunteer donors, were co-cultured with the LSCC-sEV-treated M0 macrophages to evaluate their proliferation, and immune function. The role of LSCC-sEVs was investigated in macrophage tumor-bearing mouse models. Results: LSCC-sEVs promoted TAM M2 polarization and impaired CD8+ T cell function, attributing to PD-L1 expression upregulation. In addition, suppression of metabolic reprogramming could partially reverse LSCC-sEV-induced CD8+ T cell dysfunction. STC-1 was found highly enriched in LSCC-sEVs. Knockdown of STC1 abrogated metabolic reprogramming of TAMs into M2-like macrophages and restored CD8+ T cell function. Importantly, in vivo results showed that LSCC-sEVs transform TAMs into M2 phenotype by mediating metabolic reprogramming and induce CD8+ T cell dysfunction, ultimately accelerating tumor growth. Conclusion: Our data reveal a previously undescribed role for LSCC-sEVs in the regulation of M2 polarization of TAMs and immune cell function through STC1 mediated metabolic reprogramming. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) interactions are targets for immunotherapies aimed to reinvigorate T cell function. Recently, it was documented that PD-L1 regulates dendritic cell (DC) migration through intracellular signaling events. In this study, we find that both preclinical murine and clinically available human PD-L1 antibodies limit DC migration. We show that cis interactions between PD-L1 and CD80 are critical for promoting migration and define specific regions within these proteins necessary for migration. Furthermore, we demonstrate that aPD-L1 significantly impedes DC migration in a B16 melanoma tumor model. Last, we outline how blocking cis PD-L1: CD80 interactions or mutation of the intracellular domain of PD-L1, in an imiquimod-induced murine model of psoriasis, limits DC migration to the lymph node, decreases interleukin-17 production by CD4+ T cells in the lymph node, and reduces epidermal thickening. Therefore, PD-L1 and CD80 interactions are important regulators of DC migration to the draining lymph node. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies. [ABSTRACT FROM AUTHOR]

Background: The progression of bladder cancer (BC) from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) significantly increases disease severity. Although the tumor microenvironment (TME) plays a pivotal role in this process, the heterogeneity of tumor cells and TME components remains underexplored. Methods: We characterized the transcriptomes of single cells from 11 BC samples, including 4 NMIBC, 4 MIBC, and 3 adjacent normal tissues. Bulk RNA-seq data were used to validate the clinical features of characteristic cells, and protein levels of these cells were further confirmed through immunohistochemistry (IHC) and multiplex immunofluorescence. Results: Bladder cancer progression was associated with distinct transcriptomic features in the TME. Tumor cells in MIBC displayed enhanced glycolytic activity and downregulation of chemokines and MHC-II molecules, reducing immune cell recruitment and facilitating immune evasion. This highlights glycolysis as a potential therapeutic target for disrupting tumor progression. We identified a T cell exhaustion pathway from naive CD8 + T cells (CD8 + TCF7) to terminally exhausted CD8 + STMN1 cells, with progressively declining immune surveillance. Targeting intermediate exhaustion states may restore T cell function and improve anti-tumor immunity. Macrophages polarized toward a pro-tumorigenic phenotype, while VEGFA + mast cells promoted angiogenesis in early-stage BC, suggesting their role as potential targets for therapeutic intervention in NMIBC. Furthermore, conventional dendritic cells (DCs) transformed into LAMP3 + DCs, contributing to an immunosuppressive microenvironment and enabling immune evasion. Conclusion: This study reveals dynamic changes in the TME during BC progression, including enhanced glycolysis, T cell exhaustion, and immune cell remodeling, which contribute to immune evasion and tumor progression. These findings identify critical pathways and cell populations as potential therapeutic targets, offering new strategies to improve treatment outcomes in BC patients. [ABSTRACT FROM AUTHOR]

P4-ATPases, a subfamily of the P-type ATPase superfamily, play a crucial role in translocating membrane lipids from the exoplasmic/luminal leaflet to the cytoplasmic leaflet. This process generates and regulates transbilayer lipid asymmetry. These enzymes are conserved across all eukaryotes, and the human genome encodes 14 distinct P4-ATPases. Initially identified as aminophospholipid translocases, P4-ATPases have since been found to translocate other phospholipids, including phosphatidylcholine, phosphatidylinositol, and even glycosphingolipids. Recent advances in structural analysis have significantly improved our understanding of the lipid transport machinery associated with P4-ATPases, as documented in recent reviews. In this review, we highlight the emerging evidence related to substrate diversity, the regulation of cellular localization, enzymatic activities, and their impact on organism homeostasis and diseases. This review highlights current knowledge and recent advances regarding P4-ATPases, focusing on substrate diversity, regulation of cellular localization, enzymatic activities, and their impact on organism homeostasis and diseases. [ABSTRACT FROM AUTHOR]

Bacterial extracellular vesicles (EVs) are vesicles secreted by bacteria into the extracellular environment. Containing DNA, RNA and proteins, EVs are implicated to mediate intercellular communications. The marine cyanobacterium Prochlorococcus, the most abundant photosynthetic organism in marine ecosystems, has been shown to generate EVs continuously during cell growth. However, biogenesis and functions of EVs released by Prochlorococcus remain largely unclear. Here, we isolated and characterized EVs released by Prochlorococcus MED4 culture. We found that the majority of MED4 EVs are elliptical and enriched with specific proteins performing particular cellular functions. The light–dark cycle has been demonstrated to affect the cell cycle of Prochlorococcus, with cell division occurring at night time. Interestingly, we found that the net production of MED4 EVs was faster during the night time. Moreover, we revealed that MED4 EVs that are released or absorbed in the night time are enriched with distinct proteins, suggesting the release and absorbance of EVs are influenced by the diel cycle. We found that inhibiting cell division decreased the net production of MED4 EVs during the night time, suggesting that cell division is important for the biogenesis of MED4 EVs. These analyses provide novel insights into biogenesis and functions of EVs released from bacteria. This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'. [ABSTRACT FROM AUTHOR]

Transepithelial electrical resistance (TEER) measurement is a label free, rapid and real-time technique, which is commonly used to evaluate the integrity of cell barriers. TEER characterization is important for applications, such as tissue (brain, intestines, lungs) barrier modeling, drug screening, and cell growth monitoring. Traditional TEER methods usually only show the average impedance of the whole cell layer, and lack accuracy and the characterization of internal spatial differences within cell layer regions. Here, we introduce a new spatial TEER strategy that utilizes microelectrode arrays (MEA) integrated in a Transwell to dynamically monitor TEER. A new electrical model which could reveal spatial impedance non-uniformity was proposed to extract accurate resistance from the measured data. Based on our method, the TEER signals from 16 different regions were successfully monitored in real time. The mapped impedance hotspots in different regions closely correlate with both fluorescence cell staining signals and calculated cell coverage, indicating the effectiveness of the developed spatial TEER system in monitoring local cell growth in vitro. The real-time spatial TEER responses to ethylene glycol-bis(ß-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and cisplatin were studied, which could either reduce barrier integrity or inhibit cellular growth. The obtained results demonstrated the spatial TEER's applicability for cell barrier function and cell growth monitoring. Our approach provides accurate spatial electrical information of cell barriers and holds potential applications in drug development and screening. [ABSTRACT FROM AUTHOR]

The intestinal epithelium is a rapidly self-renewing tissue; the rapid turnover prevents the invasion of pathogens and harmful components from the intestinal lumen, preventing inflammation and infectious diseases. Intestinal epithelial barrier function depends on the epithelial cell proliferation and junctions, as well as the state of the immune system in the lamina propria. Polyamines, particularly putrescine, spermidine, and spermine, are essential for many cell functions and play a crucial role in mammalian cellular homeostasis, such as that of cell growth, proliferation, differentiation, and maintenance, through multiple biological processes, including translation, transcription, and autophagy. Although the vital role of polyamines in normal intestinal epithelial cell growth and barrier function has been known since the 1980s, recent studies have provided new insights into this topic at the molecular level, such as eukaryotic initiation factor-5A hypusination and autophagy, with rapid advances in polyamine biology in normal cells using biological technologies. This review summarizes recent advances in our understanding of the role of polyamines in regulating normal, non-cancerous, intestinal epithelial barrier function, with a particular focus on intestinal epithelial renewal, cell junctions, and immune cell differentiation in the lamina propria. [ABSTRACT FROM AUTHOR]

Pathological neovascularization is a hallmark of many vision-threatening diseases. However, some patients exhibit poor responses to current anti-VEGF therapies due to resistance and limited efficacy. Recent studies have highlighted the roles of noncoding RNAs in various biological processes, paving the way for RNA-based therapeutics. In this study, we report a marked down-regulation of miR-205 under pathological conditions. miR-205 potently inhibits endothelial cell functions critical for pathological neovascularization, including proliferation, migration, and tube formation. Furthermore, miR-205 strengthens the endothelial barrier, thereby reducing vascular leakage. In mouse models of retinal and choroidal neovascularization, miR-205 administration effectively suppresses abnormal blood vessel formation and leakage. Mechanistically, miR-205 directly targets VEGFA and ANGPT2, which are key drivers of pathological neovascularization. To improve delivery, we successfully loaded miR-205 into exosomes derived from mesenchymal stem cells. This innovative approach avoids cytotoxicity while preserving therapeutic efficacy in both cellular and animal models. Collectively, our findings highlight miR-205 as a promising therapeutic for ocular neovascularization, with exosome delivery offering a novel and efficient strategy for treating vision-threatening vascular diseases. [ABSTRACT FROM AUTHOR]

Viral infections of the central nervous system (CNS) are a major cause of morbidity largely due to lack of prevention and inadequate treatments. While mortality from viral CNS infections is significant, nearly two thirds of the patients survive. Thus, it is important to understand how the human CNS can successfully control virus infection and recover. Since it is not possible to study the human CNS throughout the course of viral infection at the cellular level, here we analyzed a non-lethal viral infection in the CNS of nonhuman primates (NHPs). We inoculated NHPs intracerebrally with a high dose of La Crosse virus (LACV), a bunyavirus that can infect neurons and cause encephalitis primarily in children, but with a very low (≤ 1%) mortality rate. To profile the CNS response to LACV infection, we used an integrative approach that was based on comprehensive analyses of (i) spatiotemporal dynamics of virus replication, (ii) identification of types of infected neurons, (iii) spatiotemporal transcriptomics, and (iv) morphological and functional changes in CNS intrinsic and extrinsic cells. We identified the location, timing, and functional repertoire of optimal transcriptional and translational regulation of the primate CNS in response to virus infection of neurons. These CNS responses involved a well-coordinated spatiotemporal interplay between astrocytes, lymphocytes, microglia, and CNS-border macrophages. Our findings suggest a multifaceted program governing an optimal CNS response to virus infection with specific events coordinated in space and time. This allowed the CNS to successfully control the infection by rapidly clearing the virus from infected neurons, mitigate damage to neurophysiology, activate and terminate immune responses in a timely manner, resolve inflammation, restore homeostasis, and initiate tissue repair. An increased understanding of these processes may provide new therapeutic opportunities to improve outcomes of viral CNS diseases in humans. Author summary: Viral infections of the brain and spinal cord can be devastating and even fatal in some patients, while others survive and recover. Understanding how the human brain and spinal cord can successfully control virus infection may lead to improved treatments and help to determine the optimal timing for their use. Here, we studied how the brain and spinal cord of nonhuman primates respond to virus infection after inoculation of La Crosse virus directly into the brain. We identified the location, timing, and functional repertoire of optimal host responses in the primate brain and spinal cord that led to rapid virus clearance from infected neurons. These host responses were carefully regulated at the levels of gene expression and cellular functions to mitigate neurological damage, resolve inflammation, restore homeostasis, and initiate tissue repair. A better understanding of the processes that govern optimal responses to viral infection in the brain and spinal cord may improve outcomes of viral neurological diseases and allow full recovery in a higher proportion of patients. [ABSTRACT FROM AUTHOR]

Objective: Long-term management of people living with HIV (PLWHs) often relies on CD4+ T cell counts for assessing immune recovery, yet a single metric offers limited information. This study aimed to explore the association between the CD4/CD8 ratio and T lymphocyte activities in PLWHs. Methods: 125 PLWHs and 31 HIV-uninfected controls (UCs) were enrolled and categorized into four groups based on their CD4/CD8 ratios: extremely low ratio (ELR) group: 0.4 < CD4/CD8; low ratio (LR) group: 0.4 ≤ CD4/CD8<0.7; medium ratio (MR) group: 0.7 ≤ CD4/CD8<1; high ratio (HR) group: CD4/CD8 ≥ 1. The activation and proliferation phenotypes, mitochondrial functions, and inflammatory indexes of CD4+ T cells and CD8+ T cells were measured, and correlations between the CD4/CD8 ratio and T cell functions were analyzed. Results: T cell activation and proliferation were significantly elevated in the ELR group compared to UCs. However, the ELR group had a larger proportion of T cells with lipid peroxidation, mitochondrial lipid reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) abnormalities compared to the other groups. As the CD4/CD8 ratio increased, mitochondrial lipid peroxidation damage decreased and MMP was restored. Additionally, the ELR group had more inflammatory markers in CD4+ T cells. Correlation analysis revealed that the CD4/CD8 ratio was associated with multiple T cell functions, and its correlation coefficient with mitochondrial function was higher than that of CD4+ T cell count. Conclusion: The CD4/CD8 ratio is closely related to T lymphocyte functions and is significantly superior to the CD4+ T cell count in reflecting the mitochondrial lipid peroxidation level and mitochondrial functions within T lymphocytes. [ABSTRACT FROM AUTHOR]

Barrier tissues like the skin, gastrointestinal tract, and respiratory system exhibit high IL-33 expression. IL-33 expression increases in humans and mice during cutaneous wound healing. Following skin injury, IL-33 alerts immune cells via its receptor ST2, modulating the inflammatory response and acting as a nuclear transcription factor to regulate target cell function. Multiple studies have verified the vital function of IL-33 in cutaneous wound healing; however, the mechanisms remain contentious. This review provides an overview of the progress made in comprehending the biological characteristics of IL-33, including its production, its regulatory effects on target cells' activities, and its impact on chronic wounds. This overview aids in elucidating the mechanisms through which IL-33 contributes to wound healing, thereby offering insights into potential therapeutic strategies for treating chronic wounds. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton performs multiple cellular functions, and as such, actin polymerization must be tightly regulated. We previously demonstrated that reversible, non-degradative ubiquitylation regulates the function of the actin polymerase VASP in developing neurons. However, the underlying mechanism of how ubiquitylation impacts VASP activity was unknown. Here, we show that mimicking multi-monoubiquitylation of VASP at K240 and K286 negatively regulates VASP interactions with actin. Using in vitro biochemical assays, we demonstrate the reduced ability of multimonoubiquitylated VASP to bind, bundle, and elongate actin filaments. However, multi-monoubiquitylated VASP maintained the ability to bind and protect barbed ends from capping protein. Finally, we demonstrate the electroporation of recombinant multimonoubiquitylated VASP protein altered cell spreading morphology. Collectively, these results suggest a mechanism in which ubiquitylation controls VASP-mediated actin dynamics. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated. Objective: This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment. Methods: APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis. Results: DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy. Conclusions: DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Large B-cell lymphoma (LBCL) is a type of blood cancer that can be challenging to treat, especially when it does not respond to standard chemotherapy or relapses after treatment. New therapies, such as CAR-T cells and bispecific antibodies, have shown promise in treating these cases. However, not all patients benefit equally from these treatments, highlighting the need for new ways to predict treatment response. This study focuses on the tumor microenvironment, which includes the immune cells and molecules surrounding the LBCL tumor cells. By understanding how this environment affects CAR-T and bispecific antibody treatment outcomes, this manuscript aims to identify factors that can help predict success or resistance to therapy. These insights could lead to more personalized treatment approaches and improved outcomes for patients with LBCL. T-cell redirecting therapies, which include chimeric antigen receptor T-cells (CAR-Ts) and bispecific antibodies (BSAs), have revolutionized the treatment of relapsed\refractory large B-cell lymphoma (LBCL). Expanding clinical experience with these advanced therapies shows the potential for the optimization of their use with combination or consolidation strategies, which necessitates the prognostic stratification of patients. While traditional clinical prognostic factors identified in the era of chemotherapy are characterized by limited value, the tumor microenvironment (TME) is becoming a new prognostic cluster. We examine how the heterogeneity of LBCL, characterized by variations in tumor parameters and differences in TME immune cell composition, immune checkpoint expression, and cytokine milieu, correlates with both positive responses and resistance to treatment. While classical parameters such as histological subtype, cell of origin, and target antigen expression lack proven prognostic value for T-cell redirecting therapies, the density and functional state of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint molecules are shown to be critical determinants of therapeutic success, particularly in CAR-T therapy. We identify several gaps in the current knowledge and suggest that the insights gained from CAR-T experience could be instrumental in refining BSA applications. This report also highlights limitations in the current knowledge, as TME data derive from a limited number of registrational trials with varying methodologies, complicating cross-study comparisons and often focusing on immediate response metrics rather than long-term outcomes. By dissecting the complex interactions within the TME, this review aims to identify new prognostic factors and targets, ultimately fostering more effective and tailored treatment strategies for LBCL patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomeres play an integral role in preventing genomic instability by protecting chromosomal ends using telomeric repeats, and their dysfunction may lead to premature aging disorders and age-related diseases. During cellular division, they undergo telomere attrition, resulting in the gradual shortening of those protective caps, leading to genomic instability and cellular aging. Critically short telomeres in normal cells trigger senescence, a major contributor to age-related diseases, and opens the door for genomic instability, which promotes carcinogenesis. This review aims to provide an updated overview of telomere biology and therapeutic strategies around telomere attrition. We emphasize the importance of understanding the complex balance between preserving telomere length in aging while inhibiting telomere maintenance in cancer by proposing Optimal Therapeutic Approaches based on the most updated literature. Background/Objectives: As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. Methods: We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. Results: Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson–Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. Conclusions: The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging. [ABSTRACT FROM AUTHOR]

Simple Summary: Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis and has been implicated in several metabolic disorders and diseases. In particular, regucalcin is a novel suppressor in several cancer types. Regucalcin plays a potential role in suppressing carcinogenesis. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, thereby promoting dormancy in cancer patients. Notably, regucalcin is found in serum and extracellular fluids. Extracellular regucalcin has been shown to suppress the growth and bone metastatic activity of human cancer cells, suggesting that it plays an important role as a suppressor in the tumor microenvironment of cancer cells. Alteration of serum regucalcin levels under physiological and pathophysiological conditions may influence cancer activity in the microenvironment. This review discusses the potential role of extracellular regucalcin in cancer cell activity as a potential suppressor in the cancer microenvironment, proposing the role of exogenous regucalcin in cancer prevention and therapy. The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, there has been a paradigm shift in first-line treatment for unresectable hepatocellular carcinoma (HCC) from multitargeted tyrosine kinase inhibitors to immune checkpoint inhibitor-based therapies. Despite the unprecedented improvement in clinical outcomes, responses to these therapies are still only observed in a minority of HCC patients. In this review, we discuss the tumor intrinsic and extrinsic mechanisms of resistance to standard immune checkpoint inhibitors, explore novel approaches to optimize immunotherapy-based regimens, and highlight notable clinical trials that have the potential to change future standard care for HCC. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is an intricate condition that is caused by aberrant cell signaling regulation induced by the accumulation of genetic and epigenetic alterations. It is well known that various downstream signaling cascades (JAK/STAT, PI3K/Akt, and MAPK) are activated in transformed cells to regulate tumor growth, angiogenesis, metastasis, therapy failure, and stemness. However, the complex signaling networks and their crosstalk is challenged by structural alterations, aberrant gene amplification, and activation of alternative pathways. The complex signaling network within the breast tumor microenvironment is crucial for its growth, metastasis, angiogenesis, therapy escape, stem cell maintenance, and immunomodulation. An array of secretory factors and their receptors activate downstream signaling cascades regulating breast cancer progression and metastasis. Among various signaling pathways, the EGFR, ER, Notch, and Hedgehog signaling pathways have recently been identified as crucial in terms of breast cancer proliferation, survival, differentiation, maintenance of CSCs, and therapy failure. These receptors mediate various downstream signaling pathways such as MAPK, including MEK/ERK signaling pathways that promote common pro-oncogenic signaling, whereas dysregulation of PI3K/Akt, Wnt/β-catenin, and JAK/STAT activates key oncogenic events such as drug resistance, CSC enrichment, and metabolic reprogramming. Additionally, these cascades orchestrate an intricate interplay between stromal cells, immune cells, and tumor cells. Metabolic reprogramming and adaptations contribute to aggressive breast cancer and are unresponsive to therapy. Herein, recent insights into the novel signaling pathways operating within the breast TME that aid in their advancement are emphasized and current developments in practices targeting the breast TME to enhance treatment efficacy are reviewed. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell surface proteins and receptors on cancer cells, important as disease markers and drug targets, are highly dynamic, with their biological functions controlled by constantly changing protein–protein interaction networks. Studying these transient macromolecular neighborhoods is technically challenging, and traditional methods often fall short. Proximity labeling, a cutting-edge proteomics technology, offers a more precise approach that overcomes the limitations of existing methods. This review highlights the strategies, applications, benefits, and limitations of different proximity labeling platforms used to map the receptor protein microenvironment on the surface of cancer cells. Cell surface receptors are pivotal to cancer cell transformation, disease progression, metastasis, early detection, targeted therapy, drug responses, and clinical outcomes. Since they coordinate complex signaling communication networks in the tumor microenvironment, mapping the physical interaction partners of cell surface receptors in vivo is vital for understanding their roles, functional states, and suitability as therapeutic targets. Yet traditional methods like immunoprecipitation and affinity purification–mass spectrometry often fail to detect key but weak or transient receptor–protein interactions. Proximity labeling, a cutting-edge proteomics technology, addresses these technical challenges by enabling precise mapping of protein neighborhoods around a receptor target on the cell surface of cancer cells. This technique has been successfully applied in vitro and in vivo for proteomic mapping across various model systems. This review explores the fundamental principles, technologies, advantages, limitations, and applications of proximity labeling in cancer biology, focusing on mapping receptor microenvironments. By advancing mechanistic insights into cancer cell receptor signaling mechanisms, proximity labeling is poised to transform cancer research, improve targeted therapies, and illuminate avenues to overcome drug resistance. [ABSTRACT FROM AUTHOR]