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Background: Helicobacter pylori (H. pylori), a specific bacterium capable of surviving in the acidic environment of the stomach, has been recognized as a group of causative agents of gastric cancer. Therefore, the development of mucosal vaccines against H. pylori is expected to provide an important direction for the treatment of chronic gastritis and the prevention of gastric cancer. Methods and results: In this study, we used bacteria-like particles (BLPs) obtained by treating Lactic acid bacteria (L. lactis) with hot acid, and successfully displayed the M cell-targeted H. pylori multi-epitope purified antigen SAM-FAdE, with 90% display efficiency. In addition, BLPs-SAM-FAdE can effectively target M ​​cell models and M cells of mouse Peyer's patches (PPs) through oral immunization, promote the transport of particulate vaccines to dendritic cells (BMDCs) and stimulate their maturation, significantly increased proportion of plasma cells and germinal centers B cells. This indicates that the vaccination can induce notable antigen-specific mucosal immune responses (production of sIgA), CD4+ T cell responses (Th1/Th2/Th17) and humoral immune responses (production of serum IgG). Furthermore, oral BLPs-SAM-FAdE dramatically reduced the H. pylori adhesion and specific 16S rRNA expression of H. pylori in gastric mucosal tissue, protecting gastric tissue from damage. Conclusion: BLPs-SAM-FAdE can significantly reduce the adhesion of H. pylori in gastric mucosal tissue and inhibit gastritis and gastric damage caused by H. pylori infection. [ABSTRACT FROM AUTHOR]

Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to 'harmless' food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

• Successful adoptive T-cell immunotherapy begins with the presence of memory T cells. • Memory T cells have functional advantages for adoptive T-cell therapy. • Younger T cells positively correlate with clinical effectiveness of adoptive T cells. In recent years, immune cell therapy, particularly adoptive cell therapy (ACT), has shown superior therapeutic effects on hematologic malignancies. However, a challenge lies in ensuring that genetically engineered specific T cells maintain lasting anti-tumor effects within the host. The enduring success of ACT therapy hinges on the persistence of memory T (T M) cells, a diverse cell subset crucial for tumor immune response and immune memory upkeep. Notably, T M cell subsets at varying differentiation stages exhibit distinct biological traits and anti-tumor capabilities. Poorly differentiated T M cells are pivotal for favorable clinical outcomes in ACT. The differentiation of T M cells is influenced by multiple factors, including metabolism and cytokines. Consequently, current research focuses on investigating the differentiation patterns of T M cells and enhancing the production of poorly differentiated T M cells with potent anti-tumor properties in vitro, which is a prominent area of interest globally. This review delves into the differentiation features of T M cells, outlining their distribution in patients and their impact on ACT treatment. It comprehensively explores cutting-edge strategies to boost ACT efficacy through T M cell differentiation induction, aiming to unlock the full potential of T M cells in treating hematologic malignancies and offering novel insights for tumor immune cell therapy. [ABSTRACT FROM AUTHOR]

The development of complex molecular scaffolds with defined folding properties represents a central challenge in chemical research. Proteins are natural scaffolds defined by a hierarchy of structural complexity and have evolved to manifest unique functional characteristics; for example, molecular recognition capabilities that facilitate the binding of target molecules with high affinity and selectivity. Utilizing these features, proteins have been used as a starting point for the design of synthetic foldamers and enhanced biocatalysts, as well as bioactive reagents in drug discovery. In this account, we describe the strategies used in our group to stabilize protein folds, ranging from the constraint of bioactive peptide conformations to chemical protein engineering. We discuss the evolution of peptides into peptidomimetics to inhibit protein–protein and protein–nucleic acid interactions, and the selective chemical modification of proteins to enhance their properties for biotechnological applications. The reported peptide- and proteomimetic structures cover a broad range of molecular sizes and they highlight the importance of structure stabilization for the design of functional biomimetics. 1 Introduction 2 Constraining the Conformation of Peptides 3 Peptide-Based Covalent Protein Modifiers 4 Chemical Protein Engineering 5 Conclusions [ABSTRACT FROM AUTHOR]

The target of rapamycin(TOR)gene is closely related to metabolism and cellular aging, but it is unclear whether the TOR pathways mediate endurance exercise against the accelerated aging of skeletal muscle induced by high salt intake. In this study, muscular TOR gene overexpression and RNAi were constructed by constructing MhcGAL4/TOR-overexpression and MhcGAL4/TORUAS-RNAi systems in Drosophila. The results showed that muscle TOR knockdown and endurance exercise significantly increased the climbing speed, climbing endurance, the expression of autophagy related gene 2(ATG2), silent information regulator 2(SIR2), and pparγ coactivator 1(PGC-1α) genes, and superoxide dismutases(SOD) activity, but it decreased the expression of the TOR gene and reactive oxygen species(ROS) level, and it protected the myofibrillar fibers and mitochondria of skeletal muscle in Drosophila on a high-salt diet. TOR overexpression yielded similar results to the high salt diet(HSD) alone, with the opposite effect of TOR knockout found in regard to endurance exercise and HSD-induced age-related skeletal muscle degradation. Therefore, the current findings confirm that the muscle TOR gene plays an important role in endurance exercise against HSD-induced age-related skeletal muscle degeneration, as it determines the activity of the mammalian target of rapamycin(MTOR)/SIR2/PGC-1α and MTOR/ATG2/PGC-1α pathways in skeletal muscle. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a vital organelle responsible for protein quality control, including the folding, modification, and transport of proteins. When misfolded or unfolded proteins accumulate in the ER, it triggers endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) to restore ER homeostasis. However, prolonged or excessive ERS can lead to apoptosis. The kidneys play a crucial role in maintaining physiological functions by excreting metabolic waste, regulating blood volume, balancing electrolytes and acid-base levels, and secreting various bioactive substances. Podocytes, epithelial cells situated outside the glomerular basement membrane, are essential for maintaining the structural integrity and permeability of the glomerular filtration barrier. Previous studies have shown that ERS in podocytes can contribute to the development of diseases such as glomerulonephritis, hereditary nephropathy, and diabetic kidney disease, potentially progressing to end-stage renal disease and causing patient mortality. As such, investigating ERS in podocytes has become a key area of focus in kidney disease research. This study examines recent advancements in understanding the effects of excessive ERS on podocytes across various kidney diseases, highlights the role of podocyte ERS in disease progression, and explores the potential therapeutic benefits of targeting the UPR to manage ERS in kidney diseases, thereby providing a scientific basis for clinical interventions. [ABSTRACT FROM AUTHOR]

Natural products, recognized for their potential in disease prevention and treatment, have been integrated with advanced nano-delivery systems to create natural product-based nanomedicines, offering innovative approaches for various diseases. Natural products derived from traditional Chinese medicine have their own targeting effect and remarkable therapeutic effect on many diseases, but there are some shortcomings such as poor physical and chemical properties. The construction of nanomedicines using the active ingredients of natural products has become a key step in the modernization research process, which could be used to make up for the defects of natural products such as low solubility, large dosage, poor bioavailability and poor targeting. Nanotechnology enhances the safety, selectivity, and efficacy of natural products, positioning natural product-based nanomedicines as promising candidates in medicine. This review outlines the current status of development, the application in different diseases, and safety evaluation of natural product-based nanomedicines, providing essential insights for further exploration of the synergy between natural products and nano-delivery systems in disease treatment. [ABSTRACT FROM AUTHOR]

Background: Spermatogonia are essential for the continual production of sperm and regeneration of the entire spermatogenic lineage after injury. In mammals, spermatogonia are formed in the neonatal testis from prospermatogonia (also termed gonocytes), which are established from primordial germ cells during fetal development. Currently, the molecular regulation of the prospermatogonial to spermatogonia transition is not fully understood. Results: In this study, we examined the gene expression patterns of prospermatogonia, spermatogonia and testicular somatic cells at 4 different stages, including embryonic day (E) 12.5, E17.5 and postnatal days (P) 1 and 6, using single-cell RNA sequencing (scRNA-seq). We identified 5 different molecular states in the prospermogonial population and revealed gene expression dynamics in corresponding testicular somatic cells. Specifically, we found that prospermatogonia mainly receive signals, while Leydig cells and peritubular myoid cells are the mediators for transmitting signals, indicating their potential roles in regulating the development and differentiation of prospermatogonia. Transcription regulon analyses revealed the involvement of basic helix-loop-helix (bHLH) transcription factors in directing prospermogonial fate decisions. We then disrupted this transcription network by ectopic expression of inhibitor of differentiation 2 (Id2), which is a negative regulator of bHLH transcription factors. The overexpression of Id2 in prospermatogonia caused severe defects in the progression of prospermatogonia to spermatogonia. Conclusion: Together, these findings provide a crucial dataset for dissecting key genes that direct the establishment of the foundational spermatogonial pool and the fate transitions of different somatic cell lineages in the testis during fetal and neonatal periods of development. [ABSTRACT FROM AUTHOR]

Cancer remains a formidable global health challenge, necessitating innovative therapeutic approaches to enhance treatment efficacy and reduce adverse effects. The traditional Chinese medicine (TCM), as an embodiment of ancient wisdom, has been validated to regulate the holistic human capacity against both internal and external "evils" in accordance with TCM principles. Therefore, it stands to reason to integrate TCM into current cancer therapy paradigms, such as chemotherapy, immunotherapy, and targeted therapy. This strategy conceptually intends to circumvent the inevitable side effects derived from present treatment, alleviate the discomfort, mollify the detrimental mood and synergize tumoricidal effects of distinct approaches. However, it is still vague whether TCM exert favorable function in cancer treatment. Therefore, it is imperative to retrieve and compile the existing literature on TCM in the realm of cancer, followed by a comprehensive recapitulation and synthesis of its core findings. Recently, with the advancement of contemporary biologic and medical theory and technology, it has become both feasible and imperative to elucidate the molecular signaling mechanisms and cellular biology underlying TCM. Specifically, leveraging TCM pharmaceutic components can not only directly impact tumor biology at the molecular level, but regulate the tumor immune environment through distinct pathways. Additionally, the administration of external TCM treatments such as acupuncture and moxibustion also demonstrates beneficial effects in cancer patients. Through comprehensive analysis, we demonstrated that TCM not only potentially increases the efficacy of conventional cancer treatments, but also significantly mitigates their toxic side effects, thereby prolonging patients' prognosis and improving their living quality. Furthermore, we have underscored the challenges and prospects associated with the integration of TCM into contemporary oncological practices, placing particular emphasis on the imperative for rigorous clinical trials and molecular investigations to substantiate the efficacy and safety of these combined therapeutic approaches. This synthesis aims to pave the way for a more integrated approach to cancer treatment rooted in both traditional wisdom and cutting-edge science. [ABSTRACT FROM AUTHOR]

Development of multicellular organisms requires well-orchestrated interplay between cell-intrinsic transcription factors and cell-cell signaling. One set of highly conserved transcription factors that plays diverse roles in development is the SoxC group. C. elegans contains a sole SoxC protein, SEM-2. SEM-2 is essential for embryonic development, and for specifying the sex myoblast (SM) fate in the postembryonic mesoderm, the M lineage. We have identified a novel partial loss-of-function sem-2 allele that has a proline to serine change in the C-terminal tail of the highly conserved DNA-binding domain. Detailed analyses of mutant animals harboring this point mutation uncovered new functions of SEM-2 in the M lineage. First, SEM-2 functions antagonistically with LET-381, the sole C. elegans FoxF/C forkhead transcription factor, to regulate dorsoventral patterning of the M lineage. Second, in addition to specifying the SM fate, SEM-2 is essential for the proliferation and diversification of the SM lineage. Finally, SEM-2 appears to directly regulate the expression of hlh-8, which encodes a basic helix-loop-helix Twist transcription factor and plays critical roles in proper patterning of the M lineage. Our data, along with previous studies, suggest an evolutionarily conserved relationship between SoxC and Twist proteins. Furthermore, our work identified new interactions in the gene regulatory network (GRN) underlying C. elegans postembryonic development and adds to the general understanding of the structure-function relationship of SoxC proteins. Author summary: SoxC transcription factors play important roles in metazoan development. Abnormal expression or function of SoxC factors has been linked to a variety of developmental disorders and cancers. It is therefore critical to understand the functions of SoxC proteins in vivo. C. elegans has a single SoxC transcription factor, SEM-2, which is known to regulate a fate decision between a proliferative progenitor cell vs. a terminally differentiated cell during postembryonic mesoderm development. In this study, we report new functions of SEM-2 in postembryonic mesoderm development via our studies of a partial loss-of-function allele of sem-2. Our work uncovers new regulatory relationships between SEM-2/SoxC and the FoxF/C transcription factor LET-381, and between SEM-2/SoxC and the C. elegans Twist ortholog HLH-8. Our findings suggest that the SoxC-Twist axis, including the downstream targets of Twist, represents an evolutionarily conserved regulatory cassette important in metazoan development. [ABSTRACT FROM AUTHOR]

Virus-like particles (VLPs), as a unique form of nanocarrier, predominantly encompass hollow protein shells that exhibit analogous morphology and structure to naturally occurring viruses, yet devoid of genetic material. VLPs are considered safe, easily modifiable, and stable, making them suitable for preparation in various expression systems. They serve as precise biological instruments with broad applications in the field of medical biology. Leveraging their unique structural attributes and facile modification capabilities, VLPs can serve as an effective platform for the delivery of tumor antigens, thereby stimulating the immune system and facilitating the eradication of tumor cells. [ABSTRACT FROM AUTHOR]

Ice plant (Mesembryanthemum crystallinum L.) is a halophyte and an inducible CAM plant. Ice plant seedlings display moderate salt tolerance, with root growth unaffected by 200 mM NaCl treatments, though hypocotyl elongation is hindered in salt-stressed etiolated seedlings. Superoxide anion accumulation was prominent in cotyledons and primary leaves but decreased in root tissues over time, with no significant effect from salt treatment. Hydrogen peroxide levels initially surged in both control and salt-treated seedlings, with higher and more persistent accumulation in the salt-treated seedlings. The activities of H2O2-scavenging ascorbate-glutathione cycle enzymes ascorbate peroxidase (APX), monodehydroascorbate reductase, and dehydroascorbate reductase increased, while guaiacol-dependent peroxidase activity decreased and catalase activity showed no change, indicating APX activity as the primary response to salt stress. Salt-induced APX activities were detected mainly in the microsomal fraction for light-grown seedlings and the cytosolic fraction for etiolated seedlings, highlighting plastids as the primary site of ROS accumulation under salt stress. An RNA-seq analysis of etiolated seedlings revealed about 8% unigenes showing more than a four-fold change in expression after a 6-h 200 mM NaCl treatment. GO enrichment analysis indicated that differentially expressed genes (DEGs) with increased transcript abundance were associated with ion transport, antioxidant activity, and stress responses, while DEGs with decreased transcript abundance were linked to metabolic and biosynthesis processes such as ribosomal protein synthesis and cell wall formation. This indicates that salt stress hinders growth but enhances ion homeostasis and stress response mechanisms. The expression of all eight APX genes were induced by a 48-hour salt treatment, with varying expression patterns. For class III peroxidase family, 14 out of 53 identified unigenes qualified as DEGs. The time-course expression patterns revealed that the transcript levels of McPrx4.1, McPrx12.1, and McPrx12.3 increased, while McPrx60.3 decreased. These findings highlight the distinct roles of class III peroxidases in balancing plant growth and stress responses, advancing our understanding of the mechanisms behind salt tolerance in halophytes. This study comprehensively analyzed changes in gene expression, antioxidant enzyme activity, and ROS accumulation in ice plant seedlings. Unveiling these responses will advance our understanding of the growth–stress balance in the intrinsic salt tolerance in halophytes. [ABSTRACT FROM AUTHOR]

S-palmitoylation is a reversible and widespread post-translational modification, but its role in the regulation of ferroptosis has been poorly understood. Here, we elucidate that GPX4, an essential regulator of ferroptosis, is reversibly palmitoylated on cysteine 66. The acyltransferase ZDHHC20 palmitoylates GPX4 and increases its protein stability. ZDHHC20 depletion or inhibition of protein palmitoylation by 2-BP sensitizes cancer cells to ferroptosis. Moreover, we identify APT2 as the depalmitoylase of GPX4. Genetic silencing or pharmacological inhibition of APT2 with ML349 increases GPX4 palmitoylation, thereby stabilizing the protein and conferring resistance to ferroptosis. Notably, disrupting GPX4 palmitoylation markedly potentiates ferroptosis in xenografted and orthotopically implanted tumor models, and inhibits tumor metastasis through blood vessels. In the chemically induced colorectal cancer model, knockout of APT2 significantly aggravates cancer progression. Furthermore, pharmacologically modulating GPX4 palmitoylation impacts liver ischemia–reperfusion injury. Overall, our findings uncover the intricate network regulating GPX4 palmitoylation, highlighting its pivotal role in modulating ferroptosis sensitivity. Ferroptosis is crucial in tumor growth, metastasis, and cancer therapy response. Here, the authors reveal that reversible palmitoylation of GPX4 by ZDHHC20 and APT2 regulates ferroptosis sensitivity, offering a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Accurate gametogenesis requires the establishment of the telomere bouquet, an evolutionarily conserved, 3D chromosomal arrangement. In this spatial configuration, telomeres temporarily aggregate at the nuclear envelope during meiotic prophase, which facilitates chromosome pairing and recombination. The mechanisms governing the assembly of the telomere bouquet remain largely unexplored, primarily due to the challenges in visualizing and manipulating the bouquet. Here, using Schizosaccharomyces pombe as a model system to elucidate telomere bouquet function, we reveal that centromeres, traditionally perceived as playing a passive role in the chromosomal reorganization necessary for bouquet assembly, play a key role in the initiation of telomere bouquet formation. We demonstrate that centromeres are capable to induce telomere mobilization, which is sufficient to trigger the first stages of bouquet assembly and the meiotic transcription program in mitotic cells. This discovery highlights the finely tuned control exerted over long-distance heterochromatic regions and underscores a pivotal step in the mechanism of eukaryotic telomere bouquet formation and meiotic transcriptional rewiring. Telomeres and centromeres are specialized chromosomal regions with distinct functions. Here, the authors uncover a long-distance molecular communication between these key regions, coordinating the formation of the telomere bouquet and the initiation of the meiotic program. [ABSTRACT FROM AUTHOR]

Somatic embryogenesis (SE) is a developmental process related to the regeneration of tissue-cultured plants, which serves as a useful technique for crop breeding and improvement. However, SE in cotton is difficult and elusive due to the lack of precise cellular level information on the reprogramming of gene expression patterns involved in somatic embryogenesis. Here, we investigate the spatial and single-cell expression profiles of key genes and the metabolic patterns of key metabolites by integrated single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics (ST), and spatial metabolomics (SM). To evaluate the results of these analyses, we functionally characterized the potential roles of two representative marker genes, AATP1 and DOX2, in the regulation of cotton somatic embryo development. A publicly available web-based resource database (https://cotton.cricaas.com.cn/somaticembryo/) in this study provides convenience for future studies of the expression patterns of marker genes at specific developmental stages during the process of SE in cotton. Understanding the reprogramming of gene expression and metabolism is critical for the success of somatic embryogenesis-based plant tissue regeneration. Here, the authors report single-cell RNA-sequencing, spatial transcriptomics and spatial metabolomics analyses during cotton somatic embryo development. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer remains a significant global health challenge, characterized by poor prognosis and high mortality rates. Mitotic integrity and genomic stability are crucial in maintaining cellular homeostasis and preventing tumorigenesis. The transcription factor NKX6.3 has emerged as a potential regulator of these processes in gastric epithelial cells, prompting an investigation into its role in gastric cancer development. Methods: We employed a combination of in vitro and in vivo techniques to elucidate the impact of NKX6.3 depletion on mitotic dynamics and genomic stability in gastric epithelial cells. Quantitative real-time PCR and Western blot analyses were conducted to assess the expression of mitosis-related genes and proteins. Flow cytometry was utilized to evaluate cell cycle distribution, while immunofluorescence microscopy enabled the visualization of mitotic abnormalities. Statistical analyses, including Student's t-test and ANOVA, were performed to determine the significance of our findings. Results: Our results demonstrate that NKX6.3 depletion leads to significant mitotic defects, characterized by increased chromosome misalignment and lagging chromosomes during anaphase. These abnormalities corresponded with elevated levels of genomic instability markers, indicating compromised genomic integrity. Furthermore, the loss of NKX6.3 resulted in altered expression of key regulatory proteins involved in mitosis and DNA repair pathways, suggesting a mechanistic link between NKX6.3 and the maintenance of genomic stability in gastric epithelial cells. Depletion of NKX6.3 resulted in accelerated cell cycle progression and the formation of abnormal mitotic figures, leading to genomic instability characterized by increased DNA content and structural abnormalities. In both in vitro and xenograft models, the depletion of NKX6.3 significantly upregulated AurkA and TPX2, which correlated with gains in DNA copy number. An inverse relationship was observed between NKX6.3 expression and the levels of AurkA and TPX2 in human gastric cancer tissues. Conclusions: This study highlights the essential role of NKX6.3 in regulating mitotic integrity and genomic stability in gastric carcinogenesis. The findings suggest that targeting NKX6.3 may offer a novel therapeutic strategy for improving treatment outcomes in gastric cancer by restoring mitotic fidelity and genomic stability. Trial registration: This study was not registered. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a grave malignant condition. While radiotherapy, often in conjunction with chemotherapy, serves as a cornerstone in the management of locally advanced or metastatic cases, patient tolerance and treatment resistance frequently hinder its efficacy. Cell-in-cell structures, prevalent in various tumors, have been linked to prognosis. Hence, investigating the prognostic significance and regulatory mechanisms of genes related to these intracellular structures in esophageal cancer is imperative. The Cancer Genome Atlas (TCGA) Esophageal Cancer (ESCA) dataset served as the training set for the analysis. Differentially expressed genes (DEGs) in ESCA samples were identified, with those related to intercellular structures designated cell-in-cell-related differential expression genes (CIC-related DEGs). Cox regression analysis was employed to identify prognostic genes, categorizing samples into high- and low-risk groups based on median risk scores. Validation was conducted using the GSE53624 risk model. Established methodologies included morphological mapping, enrichment analysis, immune infiltration analysis, prognostic gene expression validation, molecular docking, and Reverse Transcription Polymerase Chain Reaction (RT-PCR) validation. Thirty-eight intersecting genes were identified between the disease and normal groups in ESCA samples. Stepwise multivariate Cox analysis pinpointed three prognostic genes: androgen receptor (AR), C-X-C motif chemokine ligand 8 (CXCL8), and epidermal growth factor receptor (EGFR). The risk model's applicability was confirmed in the GSE53624 dataset, revealing eight significantly different immune-related gene sets. Prognostic gene expression validation demonstrated significant differences between the disease and normal groups in both datasets. The proteins corresponding to the three prognostic genes interacted with gefitinib and osimertinib. RT-PCR results corroborated the differential expression of prognostic genes in esophageal cancer tissues. This study identified AR, CXCL8, and EGFR as prognostic genes and demonstrated their molecular interactions with gefitinib and osimertinib, providing a foundation for ESCA diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a major medical challenge due to its high incidence and poor prognosis. 5-Fluorouracil (5-FU), although extensively studied in the treatment of HCC and other solid tumors, has limited application as a first-line therapy for HCC due to its resistance and significant inter-patient variability. To address these issues, researchers have explored drug repurposing. One of our key findings in this endeavour was the potent anti-HCC effect of the natural product Salidroside (Sal) when co-administered with 5-FU. Sal was found to inhibit mitosis and promote cellular senescence in HCC cells via a mechanism distinct from 5-FU, specifically by inducing excessive mitophagy that led to cellular mitochondrial dysfunction. Importantly, YIPF5 was confirmed as a potential molecular target of Sal. This natural product modulated YIPF5-induced mitophagy and influenced both mitosis and senescence in HCC cells. The combination of Sal and 5-FU demonstrated significant therapeutic effects in a mouse HCC model. In conclusion, our study was not only in line with the innovative strategy of drug repurposing, but also important for drug design and natural product screening targeting the relevant pathways. [ABSTRACT FROM AUTHOR]

Introduction: Animal influenza viruses pose a danger to the general public. Eurasian avian-like H1N1 (EA H1N1) viruses have recently infected humans in several different countries and are often found in pigs in China, indicating that they have the potential to cause a pandemic. Therefore, there is an urgent need to develop a potent vaccine against EA H1N1. Methods: In this study, we report the effective intramuscular (i.m.) and/or intranasal (i.n.) vaccination of mice with a subunit influenza vaccine utilizing safe adjuvant gram-positive enhancer matrix (GEM) particles derived from the food-grade bacterium Lactococcus lactis. The hemagglutinin (HA)-protein anchor (PA) subunit vaccine can be simply mixed with GEM particles to produce vaccines. Results: After two booster injections, the i.m.+i.n. administered GEM subunit vaccine achieved hemagglutination inhibition titers in the serum that were equivalent to those observed using the conventional i.m. method. The mucosal and Th1-biased immune responses generated by the i.m. administered subunit vaccine alone were inferior to those induced by the i.n. and i.m.+i.n. administered subunit vaccines. Vaccinated mice were challenged with live viruses (G4 EA H1N1 and A/PR/8/34) to determine whether the adjuvant combination protected against the virus after vaccination with the influenza subunit vaccine. Compared to mice inoculated with HA alone, mice immunized with i.m.+i.n. or i.n. HA-PA-GEM displayed undetectable viral titers in the lungs, at 5 d after challenge. Discussion: Overall, this study not only offers other potential platforms for the generation of swine influenza vaccines, but also a theoretical foundation for vaccine vector platforms that can be utilized for future research on other infections. [ABSTRACT FROM AUTHOR]

Background: Aspergillus flavus, a seed-borne fungal pathogen, colonizes host plants and exploits nutrients, hindering the growth of seedlings such as peanut and maize. This study investigates the effectiveness of cell-free supernatants (CFSs) from the plant growth-promoting rhizobacteria (PGPR) Bacillus albus strains NNK24 and NDP61, which belong to the Bacillus cereus group, in suppressing A. flavus AF1. Results: The antifungal activity of these CFSs was attributed to their surfactant properties and chemical composition. These were characterized using rapid chemical assays and ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight/mass spectrometry (UHPLC-ESI-QTOF/MS), combined with bioinformatic tools such as Global Natural Product Social Molecular Networking (GNPS) and Natural Products Atlas (NPAtlas). Identified putative antifungal compounds included two diketopiperazines (cyclo(Pro-Leu) and cyclo(2-hydroxy-Pro-Leu)), four macrolactins (7-O-succinyl macrolactin A, 7-O-methyl-5′-hydroxy-3′-heptenoate-macrolactin, macrolactin B, and macrolactin C), two siderophores (petrobactin and bacillibactin), and three cyclic lipopeptides (kurstakin 1, 2 or 3, and 4). These compounds are hypothesized to act synergistically via multiple mechanisms, including disruption of fungal membranes, iron capture, direct antibiosis, and triggering plant immunity. Both CFSs strongly suppressed the harmful effects of A. flavus AF1 and seed-borne A. flavus on peanut and maize seedlings, reducing disease incidence (DI) and disease severity index (DSI) compared to controls. The disease control efficacy (DCE) of the CFSs was comparable to that of the commercial fungicide. Additionally, the CFSs enhanced seed germination, vigor, seedling length, and weight in both peanut and maize. Vigor index (VI) values increased by 222.4–286.0% in peanuts and 181.7–216.4% in maize at 7 days after treatment (DAT). Conclusion: CFSs of B. albus NNK24 and NDP61 show significant potential as bioprotective agents for sustainable agriculture. Importantly, their use eliminates the need for live bacterial cells from the B. cereus group, addressing biosafety concerns. [ABSTRACT FROM AUTHOR]

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER + breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER + breast cancers. [ABSTRACT FROM AUTHOR]

Background: Reovirus (RV) is an oncolytic virus with natural tropism for cancer cells. We previously showed that RV administration in multiple myeloma (MM) patients was safe, but disease control associated with viral replication in the cancer cells was not observed. The combination with proteasome inhibitors (PIs) has shown to enhance RV therapeutic activity, but the mechanisms of action have not been fully elucidated. Methods: Electron microscopy, q-RT-PCR, single-cell mass cytometry (CyTOF), flow cytometry, plaque assays, immunohistochemistry, and Western blot analysis were used to assess RV infection of both myeloma and immune cells. Immune fluorescence, flow cytometry, and luciferase reporter assays were used to assess NF-κB pathway activation upon RV treatments. Immune profiling changes, both ex vivo and in MM patients, were analyzed by flow cytometry and CyTOF analysis. T-cell receptor (TCR) sequencing was also conducted both in immune competent MM mice and in patients enrolled in a phase 1b trial per a standard 3 + 3 dose escalation schedule. Results: Here we show ex vivo and in vivo that proteasome inhibitors (PIs) potentiate reovirus replication in circulating classical monocytes, increasing viral delivery to myeloma cells. We found that the anti-viral signals in monocytes primarily rely on NF-κB activation and that this effect is impaired by the addition of PIs. Conversely, the addition of PIs to RV therapy supports immune activation and killing of MM, independently of direct PI sensitivity. To validate the importance of PIs in enhancing oncolytic viral therapy independently of their killing activity on cancer cells, we then conducted a phase 1b trial of the reovirus Pelareorep together with the PI carfilzomib in 13 heavily pretreated PI-resistant MM patients. Objective responses, which were associated with active reovirus replication in MM cells, T cell activation, and monocytic expansion, were noted in 70% of patients. Conclusions: Although characterized as immunosuppressive drugs, PIs improved RV delivery to MM cells but also enhanced anti-MM efficacy through immune-mediated killing of myeloma cells, independently of their PI sensitivity. These results highlight a more generalizable use of PIs as therapeutic companions to support oncolytic-based therapies in cancers. Trial registration: clinicaltrials.gov, NCT 02101944. [ABSTRACT FROM AUTHOR]

The skin is a barrier that protects the human body against environmental factors (physical, including solar radiation, chemicals, and pathogens). The integrity and, consequently, the effective metabolic activity of skin cells is ensured by the cell membrane, the important structural and metabolic elements of which are phospholipids. Phospholipids are subject to continuous transformation, including enzymatic hydrolysis (with the participation of phospholipases A, C, and D) to free polyunsaturated fatty acids (PUFAs), which under the influence of cyclooxygenases (COX1/2), lipoxygenases (LOXs), and cytochrome P450 (CYPs P450) are metabolized to various classes of oxylipins, depending on the type of PUFA being metabolized and the enzyme acting. The most frequently analyzed oxylipins, especially in skin cells, are eicosanoids, which are derivatives of arachidonic acid (AA). Their level depends on both environmental factors and endogenous metabolic disorders. However, they play an important role in homeostasis mechanisms related to the structural and functional integrity of the skin, including maintaining redox balance, as well as regulating inflammatory processes arising in response to endogenous and exogenous factors reaching skin cells. Therefore, it is believed that dysregulation of eicosanoid levels may contribute to the development of skin diseases, such as psoriasis or atopic dermatitis, which in turn suggests that targeted control of the generation of specific eicosanoids may have diagnostic significance and beneficial therapeutic effects. This review is the first systemic and very detailed approach presenting both the causes and consequences of changes in phospholipid metabolism leading to the generation of eicosanoids, changes in the level of which result in specific metabolic disorders in skin cells leading to the development of various diseases. At the same time, existing literature data indicate that further detailed research is necessary to understand a clear relationship between changes in the level of specific eicosanoids and the pathomechanisms of specific skin diseases, as well as to develop an effective diagnostic and therapeutic approach. [ABSTRACT FROM AUTHOR]

Purpose: Renal cell carcinoma (RCC) is a common malignancy, with patients frequently diagnosed at an advanced stage due to the absence of sufficiently sensitive detection technologies, significantly compromising patient survival and quality of life. Advances in cell-free DNA (cfDNA) methylation profiling using liquid biopsies offer a promising non-invasive diagnostic option, but robust biomarkers for early detection are current not available. This study aimed to identify methylation biomarkers for RCC and establish a DNA methylation signature-based prognostic model for this disease. Methods: High-throughput methylation sequencing was performed on peripheral blood samples obtained from 49 primarily Stage I RCC patients and 44 healthy controls. Comparative analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression methods were employed to identify RCC methylation signatures.Subsequently, methylation markers-based diagnostic and prognostic models for RCC were independently trained and validated using random forest and Cox regression methodologies, respectively. Results: Comparative analysis revealed 864 differentially methylated CpG islands (DMCGIs), 96.3% of which were hypermethylated. Using a training set from The Cancer Genome Atlas (TCGA) dataset of 443 early-stage RCC tumors and matched normal tissues, we applied LASSO regression and identified 23 methylation signatures. We then constructed a random forest-based diagnostic model for early-stage RCC and validated the model using two independent datasets: a TCGA set of 460 RCC tumors and controls, and a blood sample set from our study of 15 RCC cases and 29 healthy controls. For Stage I RCC tissue, the model showed excellent discrimination (AUC-ROC: 0.999, sensitivity: 98.5%, specificity: 100%). Blood sample validation also yielded commendable results (AUC-ROC: 0.852, sensitivity: 73.9%, specificity: 89.7%). Further analysis using Cox regression identified 7 of the 23 DMCGIs as prognostic markers for RCC, allowing the development of a prognostic model with strong predictive power for 1-, 3-, and 5-year survival (AUC-ROC > 0.7). Conclusions: Our findings highlight the critical role of hypermethylation in RCC etiology and progression, and present these identified biomarkers as promising candidates for diagnostic and prognostic applications. [ABSTRACT FROM AUTHOR]

Typical epidermodysplasia verruciformis (EV) is a rare, autosomal recessive disorder characterized by an unusual susceptibility to infection with specific skin-trophic types of human papillomavirus, principally betapapillomaviruses, and a propensity for developing malignant skin tumors in sun exposed regions. Its etiology reflects biallelic loss-of-function mutations in TMC6 (EVER1), TMC8 (EVER2) or CIB1. A TMC6-TMC8-CIB1 protein complex in the endoplasmic reticulum is hypothesized to be a restriction factor in keratinocytes for βHPV infection. However, the complex is also present in lymphocytes and its loss may compromise cellular immune control of βHPV infection. Indeed, certain primary immunodeficiencies, iatrogenic immunosuppression and AIDS are associated with the atypical form of EV. While well controlled in immunocompetent mice, murine papillomavirus MmuPV1 was first isolated from immunodeficient mice with florid skin warts, modeling atypical EV. To examine their potential as a model of typical EV, Tmc6-/-, Tmc8-/- or wildtype FVB mice were challenged with MmuPV1. At day 16 post vaginal challenge with MmuPV1, the levels of viral transcripts were similar in Tmc6-/- and Tmc8-/- mice and wildtype FVB mice, arguing against Tmc6/8 acting as intracellular restriction factors. Thereafter, greater clearance of MmuPV1 by the wildtype that the Tmc6-/- and Tmc8-/- FVB mice was evident, supporting the hypothesis that typical EV reflects a subtle cellular immune deficit. Indeed, Tmc6-/- or Tmc8-/- mice exhibit partial CD8 T cell deficits and elevated Treg. While interferon-γ production and surface CD25 were similarly elevated in CD8 T cells upon in vitro stimulation with anti-CD3/CD28, the fraction of Tmc6-/- or Tmc8-/- CD8 T cells that were dividing was lower compared to wildtype. Typical EV patients exhibit normal control of most viral infections; Tmc6-/-, Tmc8-/- and wildtype FVB mice similarly controlled vaccinia virus after skin challenge and induced neutralizing antibodies. Author summary: Typical epidermodysplasia verruciformis (EV) patients carry biallelic disabling mutations in TMC6, TMC8 or CIB1, and suffer high rates of skin cancer in UV-exposed sites associated with human betapapillomavirus (βHPV)+ plane warts. βHPV infections are common, but asymptomatic in healthy individuals. Typical EV is not associated with enhanced susceptibility to other infectious agents, and is proposed to reflect a loss of keratinocyte-intrinsic immunity specific for βHPV. Atypical EV is driven by certain inherited T cell deficits, AIDS or immunosuppressive drugs. βHPV and mouse papillomavirus MmuPV1 each lack E5, utilize similar oncogenic pathways, and synergize with UV and immunosuppression to promote skin cancer. We show establishment of MmuPV1 infection is similar to wildtype FVB mice, but thereafter more persistent in Tmc6-/- or Tmc8-/- mice. Tmc6-/- or Tmc8-/- mice exhibit partial CD8 T cell deficits and elevated Treg, but normal control of vaccinia, implying typical EV actually reflects subtle T cell dysfunction. [ABSTRACT FROM AUTHOR]

We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.Anti-PD1 monotherapy shows limited efficacy against HER2+ tumors. Here, the authors show that murine CAR macrophages (CAR-M) induce tumor microenvironment remodeling, T-cell mediated immunity and synergy with PD1 blockade, improving survival in immunocompetent female-mouse models of HER2+ solid tumors. [ABSTRACT FROM AUTHOR]

Introduction Inhalation drug delivery can deliver high doses of chemotherapeutic drugs to the lung tumor. This study evaluates the efficacy and the mechanistic pathways of nebulized Cur NPs at various sizes to treat multidrug resistant lung cancer. Methods and results Cur-NPs (30 nm and 200 nm) were nebulized separately onto the multidrug-resistant lung cancer cells (H69AR). Smaller NPs induced significantly higher cell death owing to a higher rate of particle internalization via dynamin-dependent clathrin-mediated endocytosis. Owing to the higher lysosome trafficking of Cur-NP30 nm compared to Cur-NP200 nm, oxidation of lysosome was higher (0.47 ± 0.08 vs 0.38 ± 0.08), contributing to significantly higher mitochondrial membrane potential loss (1.57 ± 0.17 vs 1.30 ± 0.11). MRP1 level in H69AR cells was reduced from 352 ± 12.3 ng/µg of protein (untreated cells) to 287 ± 12 ng/µg of protein (Cur-NP30 nm) and 303 ± 13.4 ng/µg of protein (Cur-NP200 nm). NF-κB, and various cytokine expressions were reduced after treatment with nebulized Cur-NPs. Conclusions Nebulized Cur-NPs formulations could be internalized into the H69AR cells. The Cur-NPs toxicity toward the H69AR was size and time-dependent. Cur-NP30 nm was more effective than Cur-NP200 nm to retain within the cells to exert higher oxidative stresss-induced cell death. [ABSTRACT FROM AUTHOR]

Background: Saidi sheep are one of the most important farm animals in Upper Egypt, particularly in the Assiut governorate. Since they can provide meat, milk, fiber, and skins from low-quality roughages, sheep are among the most economically valuable animals bred for food in Egypt. Regarding breeding, relatively little is known about the Saidi breed. In mammals, the uterus is a crucial reproductive organ. Therefore, the purpose of this work was to provide further details on the histological, histochemical, and immunohistochemical analyses of superoxide dismutase 2 (SOD2), glutathione reductase (GR), and progesterone receptor alpha (PRA) as well as terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay (TUNEL) of the uterus during the follicular phase of estrous cycle in Saidi sheep. Thus, 11 healthy Saidi ewes (38.5 ± 2.03 kg weight) ranging in age from 2 to 5 years were used to examine the histological changes in the uterus. Results: In Saidi sheep, the uterine histological and immunological picture during the follicular phase of the estrous cycle was characterized by epithelial and stromal proliferation and apoptosis. Leucocytic recruitment (lymphocytes, plasma, and mast cells) was also observed. Uterine gland adenogenesis, vascular angiogenesis, oxidative marker expression, and PRA expression in the muscles, stroma, and epithelium were the most noticeable features of the follicular phase. Conclusion: This study provides new evidence of the role of PRA, SOD2, GR, and mast cells in controlling uterine epithelial proliferation and apoptosis in the Saidi sheep during the follicular phase of the estrus cycle. These findings have growing significance in understanding the key mechanisms that characterize successful reproduction and enhancing the fertility and reproductive efficiency in Saidi Sheep. [ABSTRACT FROM AUTHOR]

Background: Landslides, among the most catastrophic natural hazards, result from natural and anthropogenic factors, causing substantial financial losses, infrastructural damage, fatalities, and environmental degradation. Uttarakhand, with its unique topographical and hydrological conditions, unplanned human settlements, and changing precipitation patterns, is highly susceptible to landslides. Methods: This study evaluates landslide susceptibility for Uttarakhand, a Himalayan state in India, by employing bivariate analysis, multi-criteria decision-making, and advanced machine learning models, such as Random Forest and Extreme Gradient Boosting (XGBoost). A total of sixteen landslide influencing factors were used for performing landslide hazard susceptibility zonation, including the innovative use of geomorphons for detailed terrain analysis. Results: Approximately 18.47% of the study area was classified as high to very high landslide susceptibility zones, and 21% was classified into the moderate susceptibility category. High to very high susceptibility zones were concentrated in the Uttarkashi, Chamoli, and Pithoragarh districts of the Lesser and Higher Himalayas, areas characterized by rangelands and high annual rainfall. Conversely, very low to low susceptibility zones were predominantly located in the Tarai-Bhabar and Sub-Himalayan districts, including Haridwar and Udham Singh Nagar. The Random Forest and XGBoost models demonstrated superior predictive performance. Conclusions: The spatially explicit landslide susceptibility maps provide critical insights for urban planners, disaster management agencies, and environmentalists, aiding in developing effective strategies for landslide risk reduction and promoting sustainable development in Uttarakhand. This study exemplifies applying advanced analytical techniques to address landslide susceptibility and related soil erosion and water resource management challenges in Uttarakhand. [ABSTRACT FROM AUTHOR]

Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)—voltage-dependent anion channel 1 (VDAC1)—mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)—AMP-activated protein kinase (AMPK)—dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism. Author summary: PRRSV poses a major threat to the global swine industry, and no effective vaccines or antiviral drugs have been developed. A deep understanding of the PRRSV replication mechanism is essential for devising effective strategies to control this disease. The present work presents a detailed map of PRRSV infection, focusing on mitochondrial Ca2+, mitochondrial morphology, and glucose metabolism. Experimental findings reveal that viral infection induces alterations in fission and mitophagy through the elevation of mitochondrial Ca2+ levels. Furthermore, the study characterizes the regulatory mechanism of Ca2+ within mitochondria, influencing mitochondrial morphology during PRRSV infection. These mitochondrial alterations, coupled with reprogramming of cellular glucose metabolism, support the replication of the virus within host cells. This study provides insights into the interplay among the virus, mitochondrial morphology, and host cell metabolism, offering promise for guiding future research and informing therapeutic interventions against PRRSV. [ABSTRACT FROM AUTHOR]

Four salicylidene-based dual-responsive chemosensors 1,5-bis(5-bromosalicylaldehyde)carbohydrazone (R1), 1,5-bis(5-bromosalicylaldehyde)thiocarbohydrazone (R2), 1,5-bis(3-ethoxysalicylaldehyde)carbohydrazone (R3) and 1,5-bis(3-ethoxysalicylaldehyde)thiocarbohydrazone (R4) were synthesized and characterized. The molecular structures of R1 and R3 were confirmed by single crystal X-ray diffraction technique, which crystallized in the orthorhombic Pbcn and monoclinic P21/n space groups, respectively. The chemosensor molecules were investigated for their recognition properties against the selected cations (K+, Ca2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Fe3+ and Al3+) and anions (F−, Cl−, Br−, I−, HSO4−, H2PO4−, ClO4−, N3− and NO3−) by colorimetry, absorption spectroscopy, fluorescence spectroscopy, 1H NMR spectroscopy and theoretical studies. The sensor molecules showed colorimetric responses for the Co2+, Ni2+, Cu2+ and Fe3+ cations and the F− anion. Interestingly, the Zn2+ and Al3+ cations showed only the 'turn on' fluorometric response, whereas the F− anion showed both colorimetric and fluorometric responses. The binding constants were determined using the Benesi–Hildebrand (B–H) equation from the fluorescence titrations and found to be higher for R3 towards the Al3+ cation (2.03 × 106 M−1) with a low limit of detection (1.79 μM) and for R4 towards the F− anion (5.13 × 105 M−1) with a low limit of detection (5.23 μM). The chemosensors established 1 : 2 and 1 : 1 binding stoichiometries with the sensed cations and anion, respectively, as confirmed by Job's plots. The computational studies show a lower band gap of HOMO–LUMO when the chemosensors bind with the sensed inorganic ions compared to the free chemosensors. Furthermore, the observed fluorescent behaviour of the Zn2+ and Al3+ cations have motivated us to investigate the practical applications in the live cell-imaging of zebrafish larvae as well as in the development of a molecular logic gate. [ABSTRACT FROM AUTHOR]

Nanoparticle-based antigen carrier systems have become a significant area of research with the advancement of nanotechnology. Biodegradable polymers have emerged as particularly promising carrier vehicles due to their ability to address the limitations of existing vaccine systems. In this study, we successfully encapsulated the G5-24 linear peptide, located between amino acids 253 and 275 in the primary sequence of the rabies virus G protein, into biodegradable and biocompatible PLGA copolymer using the double emulsion solvent evaporation method. The resulting nanoparticles had a size of approximately 230.9 ± 0.9074 nm, with a PDI value of 0.168 ± 0.017 and a zeta potential value of −9.86 ± 0.132 mV. SEM images confirmed that the synthesized nanoparticles were uniform in size and distribution. Additionally, FTIR spectra indicated successful peptide loading into the nanoparticles. The encapsulation efficiency of the peptide-loaded nanoparticles was 73.3%, with a peptide loading capacity of 48.2% and a reaction yield of 30.4%. Peptide release studies demonstrated that 65.55% of the peptide was released in a controlled manner over 28 d, following a 'biphasic burst release' profile consistent with the degradation profile of PLGA. This controlled release is particularly beneficial for vaccine studies. Cytotoxicity tests revealed that the R-NP formulation did not induce cytotoxicity in fibroblast cells and enhanced NO production in macrophages, indicating its potential for vaccine development. [ABSTRACT FROM AUTHOR]

The lack of effective therapies for visual restoration in Retinitis pigmentosa and macular degeneration has led to the development of new strategies, such as optogenetics and retinal prostheses. However, visual restoration is poor due to the massive light-evoked activation of retinal neurons, regardless of the segregation of visual information in ON and OFF channels, which is essential for contrast sensitivity and spatial resolution. Here, we show that Ziapin2, a membrane photoswitch that modulates neuronal capacitance and excitability in a light-dependent manner, is capable of reinstating, in mouse and rat genetic models of photoreceptor degeneration, brisk and sluggish ON, OFF, and ON-OFF responses in retinal ganglion cells evoked by full-field stimuli, with reactivation of their excitatory and inhibitory conductances. Intravitreally injected Ziapin2 in fully blind rd10 mice restores light-driven behavior and optomotor reflexes. The results indicate that Ziapin2 is a promising molecule for reinstating physiological visual responses in the late stages of retinal degeneration. Here authors demonstrate Ziapin2, a membrane-targeted photoswitch, reinstates physiological ON/OFF light responses in retinal ganglion cells from degenerate retinas, and restores light-driven behavior and optomotor reflexes in fully blind rd10 mice. [ABSTRACT FROM AUTHOR]

Ischemic stroke constitutes a multifaceted neurological affliction that spans various cellular types. Lack of dynamic chromatin accessibility data after stroke is one of the obstacles to understanding this process. To gain insights into the variations in transcriptional regulation among various cell types subsequent to a stroke, we employed single-nucleus ATAC-seq to curate a chromatin accessibility compendium from the cerebral cortex of mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Tissue samples were collected at various time points including 0, 6, 12, 24 hours, and 7, 14 days post-reperfusion, in addition to Sham control group. We obtained 99,271 high-quality nuclei across nine cell types, thereby establishing the single-nucleus chromatin accessibility atlas. This atlas provides data for interpreting the regulatory mechanisms that pervade the continuum of ischemic stroke. The data presented herein constitutes a valuable resource for the comprehension of regulatory interplays within the pathology-afflicted cerebrum. [ABSTRACT FROM AUTHOR]

Drought adversely affects the growth and performance of plants. By contrast, the application of organic modifiers can improve plant growth by supplying nutrients and water. The influence of foliar application of organic fertilizer under water deficit conditions on growth traits, chemical composition, and fruit quality of tomato (Lycopersicon esculentum Mill., var. Maya) were investigated in greenhouse conditions based on bi-plot and principal component analysis (PCA). Plants which were cultivated in soil under greenhouse conditions were subjected to four levels foliar spraying of Zargreen liquid organic fertilizer, ZLOF (0, 2.5, 5, and 7.5 L 1000−1, shown as Z0, Z2.5, Z5, and Z7.5, respectively), and three levels of soil water, SW (100, 75, and 50% of field capacity (FC), shown W100, W75, and W50, respectively). The results of biplot analysis using the different treatments representing 42.9% and 38.3%, 60.3% and 28.8%, and 63.1% and 22.4% of the variance attributed to the first two principal components (PCs) for the PC1 and PC2, under 100, 75, and 50% FC conditions, respectively. Water deficit induced a reduction of fruit dry, and fresh weights. Application of 2.5, 5, and 7.5 L 1000−1 of the organic fertilizer significantly increased fruit fresh weight by 16, 20, and 22% and fruit dry weight by 13, 20, and 20% as compared to that of control, respectively. Vitamin C content of fruit significantly increased by 16 and 33% when respectively 5 and 7.5 L 1000−1 of the organic fertilizer was foliar sprayed. Besides, fruit iron (Fe), sodium (Na (and potassium (K) concentrations increased with the application of the organic fertilizer at different levels of water deficit. Furthermore, the highest fruit zinc (Zn) concentration was obtained at the highest level of both applied organic fertilizer and water deficit. The best treatments were selected with increased PC1 and decreased PC2 for different water conditions. The W100Z7.5, W75Z7.5, and W50Z5 treatments with the higher PC1 and the lower PC2, also exhibited higher scores for fruit dry weight, and Na and K concentrations under W100; vitamin C, number of fruits, fruit fresh weight, and fruit Fe concentration under W75; citric acid, and fruit Fe, Zn, Na, K, and Cu concentrations under W50 treatment. The addition of the organic fertilizer was effective in enhancing the plant growth traits under water deficit conditions. Therefore, it can be concluded that organic fertilizer addition is an effective management strategy to mitigate the adverse effects of drought and improve the quantity and quality of tomato fruit. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men in the United States. While PCa initially responds to androgen deprivation therapy, a significant portion progresses to castration-resistant PCa. Approximately 20–25% of these cases acquire aggressive neuroendocrine (NE) features, ultimately leading to neuroendocrine prostate cancer (NEPC). In this study, we investigated the expression of stathmin 1 (STMN1) across PCa subtypes using bioinformatics, western blotting, and immunohistochemical staining analyses in human and murine models. We found that elevated STMN1 expression correlated with high Gleason Scores, increased cell proliferation, and poor clinical outcomes in PCa patients. Notably, STMN1 expression was significantly higher in NEPC compared to prostate adenocarcinoma, suggesting its role in NEPC progression. Findings from TRAMP tumors, a murine NEPC model, further supported these results. In conclusion, STMN1 expression is elevated in advanced PCa, particularly in NEPC, suggesting its involvement in the progression of aggressive forms of PCa. While STMN1 shows potential as a diagnostic and prognostic marker for aggressive PCa, further studies are necessary to establish its clinical utility. [ABSTRACT FROM AUTHOR]

Deer antler-derived reserve mesenchyme cells (RMCs) are a promising source of cells for cartilage regeneration therapy due to their chondrogenic differentiation potential. However, the regulatory mechanism has not yet been elucidated. In this study, we analyzed the role of microRNAs (miRNAs) in regulating the differentiation of RMCs and in the post-transcriptional regulation of chondrogenesis and hypertrophic differentiation at the molecular and histological levels. The results showed that RMCs showed typical MSC differentiation potentials. During chondrogenic differentiation, we obtained the expression profile of miRNAs, among which miR- 145 was the most prominent candidate as a key microRNA involved in the balance of chondral and endochondral differentiation. Knockdown of miR-145 promoted chondrogenesis and inhibited hypertrophy differentiation in RMCs. Mechanically, by prediction through online databases combined with dual-luciferase reporter assay, SOX9 was suggested as a target of miR-145. Further validation experiments confirmed that knockdown of miR-145 contributed to the balance between endochondral versus chondral differentiation of RMCs by targeting SOX9. Additionally, RMCs transfected with the miR-145-knockdown-mediated lentiviral vector successfully promoted cartilage regeneration in vivo. In summary, our study suggested that the reciprocal negative feedback between SOX9 and miR-145 was essential for balancing between endochondral versus chondral differentiation of RMCs. Our study suggested that modification of RMCs using miRNAs transduction might be an effective treatment for cartilage defects. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) continues to be a major cause of cancer-related death worldwide, primarily due to delays in diagnosis and resistance to existing treatments. Recent research has identified ATP-dependent chromatin remodeling-related genes (ACRRGs) as promising targets for therapeutic intervention across various types of cancer. This development offers potential new avenues for addressing the challenges in HCC management. Methods: This study integrated bioinformatics analyses and experimental approaches to explore the role of ACRRGs in HCC. We utilized data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), applying machine learning algorithms to develop a prognostic model based on ACRRGs' expression. Experimental validation was conducted using quantitative real-time Polymerase Chain Reaction (qRT-PCR), Western blotting, and functional assays in HCC cell lines and xenograft models. Results: Our bioinformatics analysis identified four key ACRRGs—MORF4L1, HDAC1, VPS72, and RUVBL2—that serve as prognostic markers for HCC. The developed risk prediction model effectively distinguished between high-risk and low-risk patients, showing significant differences in survival outcomes and predicting responses to immunotherapy in HCC patients. Experimentally, MORF4L1 was demonstrated to enhance cancer stemness by activating the Hedgehog signaling pathway, as supported by both in vitro and in vivo assays. Conclusion: ACRRGs, particularly MORF4L1, play crucial roles in modulating HCC progression, offering new insights into the molecular mechanisms driving HCC and potential therapeutic targets. Our findings advocate for the inclusion of chromatin remodeling dynamics in the strategic development of precision therapies for HCC. [ABSTRACT FROM AUTHOR]