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Simple Summary: Metabolic reprogramming in HER2-positive breast cancer is associated with acquired resistance to targeted therapies. Thus, targeting dysregulated metabolic pathways in cancers is highly beneficial. In this study, we examined the anti-tumor effects of an LXR inverse agonist GAC0001E5 (1E5) in HER2-positive breast cancer in vitro. Strikingly, we observed disruption of two major pathways, glutaminolysis and de novo lipogenesis, leading to oxidative stress and cell death. Additionally, we discovered the indirect effects of 1E5 in downregulating HER2 expression through fatty acid synthase (FASN). Moreover, in combinatory treatments of 1E5 and lapatinib, 1E5 potentiates lapatinib's effects. These findings indicate the importance of 1E5 as a metabolic disruptor in HER2-positive breast cancer. The HER2-positive subtype accounts for approximately one-fifth of all breast cancers. Insensitivity and development of acquired resistance to targeted therapies in some patients contribute to their poor prognosis. HER2 overexpression is associated with metabolic reprogramming, facilitating cancer cell growth and survival. Novel liver X receptor (LXR) ligand GAC0001E5 (1E5) has been shown to inhibit cancer cell proliferation by disrupting glutaminolysis and inducing oxidative stress. In this study, HER2-positive breast cancer cells were treated with 1E5 to determine their potential inhibitory effects and mechanisms of action in HER2-positive breast cancers. Similar to previous observations in other cancer types, 1E5 treatments inhibited LXR activity, expression, and cancer cell proliferation. Expression of fatty acid synthesis genes, including fatty acid synthase (FASN), was downregulated following 1E5 treatment, and results from co-treatment experiments with an FASN inhibitor suggest that the same pathway is targeted by 1E5. Treatments with 1E5 disrupted glutaminolysis and resulted in increased oxidative stress. Strikingly, HER2 transcript and protein levels were both significantly downregulated by 1E5. Taken together, these findings indicate the therapeutic potential of targeting HER2 overexpression and associated metabolic reprogramming via the modulation of LXR in HER2-positive breast cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cancer (OC) is one of the most prevalent cancers in the world. Despite improvements in therapies, OC still has a poor survival rate of about 50%, with metastasis being the worst-case scenario. Thus, there is an urgent need to understand the disease process and to develop diagnostic and therapeutic strategies for OC. Advancement of high throughput genome sequencing shows that more than 90% of the human genome encodes non-coding transcripts that do not code for any protein. In this review, we discuss the role of various types of these non-coding RNAs (ncRNAs) in OC and their promising clinical implications. Dysregulated expressions of ncRNAs are associated with OC initiation and progression, as well as therapy resistance. Differential expressions of these ncRNAs in blood or saliva have indicated their potential diagnostic and prognostic importance. In this review, we have summarized all the promising aspects of ncRNAs in the management of OC. Oral cancer (OC) is among the most prevalent cancers in the world. Certain geographical areas are disproportionately affected by OC cases due to the regional differences in dietary habits, tobacco and alcohol consumption. However, conventional therapeutic methods do not yield satisfying treatment outcomes. Thus, there is an urgent need to understand the disease process and to develop diagnostic and therapeutic strategies for OC. In this review, we discuss the role of various types of ncRNAs in OC, and their promising clinical implications as prognostic or diagnostic markers and therapeutic targets. MicroRNA (miRNA), long ncRNA (lncRNA), circular RNA (circRNA), PIWI-interacting RNA (piRNA), and small nucleolar RNA (snoRNA) are the major ncRNA types whose involvement in OC are emerging. Dysregulated expression of ncRNAs, particularly miRNAs, lncRNAs, and circRNAs, are linked with the initiation, progression, as well as therapy resistance of OC via modulation in a series of cellular pathways through epigenetic, transcriptional, post-transcriptional, and translational modifications. Differential expressions of miRNAs and lncRNAs in blood, saliva or extracellular vesicles have indicated potential diagnostic and prognostic importance. In this review, we have summarized all the promising aspects of ncRNAs in the management of OC. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer (OVCA) is a fatal gynecological disease for which there is no early detection test. Glucose-regulated protein 78 (GRP78), a protein marker of stress, increases during chronic stress. Chronic stress has been suggested as a hallmark of cancer development. This study examined whether expression of GRP78 is associated with development of OVCA and whether GRP78 can predict OVCA at early stage. This study found GRP78 expression and its secretion in blood increased during OVCA development and progression. This study also developed a GRP78-targeted ultrasound scanning agent that detected ovarian tumors at early stages. Thus, a woman with high levels of GRP78 in her blood may be referred to have targeted-ultrasound scanning for confirming if she has ovarian tumors. These results will be a foundation for a clinical study to examine the feasibility of GRP78 as a potential marker of blood and ultrasound scanning for early detection of OVCA. Background: Understanding malignant transformation associated with ovarian cancer (OVCA) is important to establish early detection tests. This study examined whether expression of glucose-regulated protein 78 (GRP78, marker of cellular stress) increases during OVCA development, and whether GRP78 can be detected by targeted-transvaginal ultrasound (TVUS) imaging. Methods: Normal ovaries (n = 10), benign (n = 10) and malignant ovarian tumors at early (n = 8) and late stages (n = 16), hens with and without ovarian tumors at early and late stages (n = 10, each) were examined for GRP78 expression during OVCA development by immunohistochemistry, immunoblotting, gene expression and immunoassay. Feasibility of GRP78-targeted TVUS imaging in detecting early OVCA was examined. Results: Compared with normal ovaries and benign tumors, intensity of GRP78 expression was higher (p < 0.0001) in OVCA patients. Compared with normal (9007.76 ± 816.54 pg/mL), serum GRP78 levels were significantly higher (p < 0.05) in patients with early (12,730.59 ± 817.35 pg/mL) and late-stage OVCA (13,930.12 ± 202.35) (p < 0.01). Compared with normal (222.62 ± 181.69 pg/mL), serum GRP78 levels increased (p < 0.05) in hens with early (590.19 ± 198.18 pg/mL) and late-stage OVCA (1261.38 ± 372.85) (p < 0.01). Compared with non-targeted, GRP78-targeted imaging enhanced signal intensity of TVUS (p < 0.0001). Conclusions: Tissue and serum levels of GRP78 increase in association with OVCA. GRP78 offers a potential serum and imaging marker for early OVCA detection. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer (OVCA) is one of the most fatal gynecologic malignancies with most cases detected in late stages. High mortality rates are due, in part, to the lack of an effective early detection test. Tumor development and progression are associated with an increase in the expression of tissue proteins and/or their release into circulation. These proteins may offer potential markers for the early detection of OVCA. Nucleolin, a nuclear protein, is one such marker. This pilot study examined whether the tissue expression of nucleolin and its serum levels change in association with OVCA development and progression by using archived clinical samples and the laying hen model of spontaneous OVCA. Nucleolin was found to be highly expressed in ovaries and fimbriae with tumors and in serum levels compared to those without OVCA. This study also found that tumor-associated serum levels of nucleolin increase even before the tumor forms a detectable solid mass in the ovary or fimbria, suggesting that nucleolin may be involved in malignant transformation. A smaller sample size is a limitation of this study; however, it will lay the foundation for clinical studies with larger cohorts to examine the efficacy of nucleolin as a potential serum marker for the early detection of OVCA. Objective: Ovarian high-grade serous carcinoma (HGSC) is a fatal malignancy of women. Alterations in the expression of nuclear proteins are early steps in malignant transformation; nucleolin is one such protein. Changes in nucleolin expression and circulatory levels during ovarian HGSC development are unknown. The study goal was to determine if tissue and circulatory levels of nucleolin change in response to malignant transformation leading to ovarian HGSC. Methods: Sera, ovaries, and BRCA+ fimbria from healthy subjects, and sera and tumor tissues from patients (n = 10 each), and healthy hens and hens with HGSC were examined in exploratory and prospective studies for nucleolin expression by immunohistochemistry, immunoblotting, gene expression, and immunoassay, and analyzed by analysis of variance (ANOVA). Results: Compared with normal, nucleolin expression was higher in patients and hens with ovarian HGSC and in women with a risk of HGSC (P < 0.05). Compared with normal (1400 + 105 pg/mL, n = 8), serum nucleolin levels were 1.5 and 1.7-fold higher in patients with early- (n = 5) and late-stage (n = 5) HGSC, respectively. Additionally, serum nucleolin levels increased significantly (P < 0.05) prior to the formation of detectable masses. Conclusion: This pilot study concluded that tissue and serum levels of nucleolin increase in association with malignant changes in ovaries and fimbriae leading to ovarian HGSC. [ABSTRACT FROM AUTHOR]

Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and evaluated changes in gene expression (mRNA) and regulation (microRNA/miRNA) following LVAD. LV and RV free-wall tissues were collected from end-stage DCM hearts with (n = 8) and without LVAD (n = 8). Non-failing control tissues were collected from donated hearts (n = 6). Gene expression (for mRNAs/miRNAs) was determined using microarrays. Our results demonstrate that immune response, oxygen homeostasis, and cellular physiological processes were the most enriched pathways among differentially expressed genes in both ventricles of end-stage DCM hearts. LV genes involved in circadian rhythm, muscle contraction, cellular hypertrophy, and extracellular matrix (ECM) remodelling were differentially expressed. In the RV, genes related to the apelin signalling pathway were affected. Following LVAD use, immune response genes improved in both ventricles; oxygen homeostasis and ECM remodelling genes improved in the LV and, four miRNAs normalized. We conclude that LVAD reduced the expression and induced additional transcriptomic changes of various mRNAs and miRNAs as an integral component of the reverse ventricular remodelling in a chamber-specific manner. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary bone cancers like osteosarcoma (OS) are driven by bone cells that develop mutations, and behave in an uncontrolled manner. All bone cells, including defective ones, are sensitive to their physical environment. We tested the response of osteosarcoma cells, at the gene level, to two different kinds of mechanical stimulus, which are relevant to the tumor microenvironment. The first was fluid flowing over their surface, and the second was stiffness or rigidity of the surface beneath. In our study we found that fluid flow in particular has the ability to change the behavior of OS cancer cells, and could potentially be used to reduce their harmful effects. Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness—two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in the osteoblast lineage. We silenced Sox2 (which regulates YAP) and tested the effect of fluid flow shear stress (FFSS) and substrate stiffness on YAP expression/activity—which was significantly reduced by loss of Sox2, but that effect was reversed by FFSS but not by substrate stiffness. Osteogenic gene expression was also reduced in the absence of Sox2 but again this was reversed by FFSS and remained largely unaffected by substrate stiffness. Thus we described the effect of two distinct stimuli on the mechanosensory and osteogenic profiles of OS cells. Taken together, these data suggest that modulation of fluid movement through, or stiffness levels within, OS tumors could represent a novel consideration in the development of new treatments to prevent their progression. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent decades, advancements in high-throughput sequencing technology, coupled with reduced sequencing costs, have led to a significant increase in the genomic profiling of benign and malignant peripheral nerve sheath tumors. This review synthesizes recent sequencing discoveries from multiple sequencing technologies, underscores the critical mutation events involved in tumor pathogenesis, and explores their potential therapeutic implications. By elucidating the molecular basis of these tumors, clinicians and researchers can improve patient outcomes and provide a foundation for more effective treatment strategies. Malignant peripheral nerve sheath tumors (MPNSTs) are rare but aggressive malignancies with a low 5-year survival rate despite current treatments. MPNSTs frequently harbor mutations in key genes such as NF1, CDKN2A, TP53, and PRC2 components (EED or SUZ12) across different disease stages. With the rapid advancement of high-throughput sequencing technologies, the molecular characteristics driving MPNST development are becoming clearer. This review summarizes recent sequencing studies on peripheral nerve sheath tumors, including plexiform neurofibromas (PNs), atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP), and MPNSTs, highlighting key mutation events in tumor progression from the perspectives of epigenetics, transcriptomics, genomics, proteomics, and metabolomics. We also discuss the therapeutic implications of these genomic findings, focusing on preclinical and clinical trials targeting these alterations. Finally, we conclude that overcoming tumor resistance through combined targeted therapies and personalized treatments based on the molecular characteristics of MPNSTs will be a key direction for future treatment strategies. [ABSTRACT FROM AUTHOR]

The fungus Puccinia triticina Eriks (Pt) is the cause of leaf rust, one of the most damaging diseases, which significantly reduces common wheat yields. In Pt-resistant adult plants, an APR-type resistance is observed, which protects the plant against multiple pathogen races and is distinguished by its persistence under production conditions. With a more complete understanding of the molecular mechanisms underlying the function of APR genes, it will be possible to develop new strategies for resistance breeding in wheat. Currently, mainly APR genes, such as Lr34, Lr46, and Lr67, are principally involved in resistance breeding as they confer durable resistance to multiple fungal races occurring under different climatic and environmental conditions. However, the mechanisms underlying the defence against pathogens mediated by APR genes remain largely unknown. Our research aimed to shed light on the molecular mechanisms related to resistance genes and miRNAs expression, underlying APR resistance to leaf rust caused by Pt. Furthermore, the present study aimed to identify and functionally characterize the investigated miRNAs and their target genes in wheat in response to leaf rust inoculation. The plant material included hybrid forms of wheat from the F2 and BC1F1 generations, obtained by crossing the resistance cultivar Glenlea (CItr 17272) with agriculturally important Polish wheat cultivars. Biotic stress was induced in adult plants via inoculation with Pt fungal spores under controlled conditions. The RT-qPCR method was used to analyze the expression profiles of selected APR genes at five time points (0, 6, 12, 24, and 48 hpi). The results presented here demonstrate the differential expression of APR genes and miRNAs at stages of leaf rust development at selected timepoints after inoculation. We analyzed the expression of three leaf rust resistance genes, using different genetic backgrounds in F2 and BC1F1 segregation materials, in leaf tissues after Pt infection. Our goal was to investigate potential differences resulting from the genetic background found in different generations of hybrid forms of the same parental forms. Gene ontology analysis predicted 190 target genes for tae-miR5384-3p and 167 target genes for tae-miR9653b. Our findings revealed distinct expression profiles for genes, with the highest expression levels observed mainly at 6, 24, and 48 hpi. The candidate gene Lr46-Glu2 displayed an upregulation, suggesting its potential involvement in the immune response against Pt infection. [ABSTRACT FROM AUTHOR]

Light is an important environmental factor affecting the ripening and quality of strawberry fruit. Previous studies have shown that red light treatment can promote strawberry ripening. Gene expression is closely associated with chromatin openness, and changes in chromatin accessibility are crucial for the binding of transcription factors to downstream regulatory sequences. However, the changes in chromatin accessibility in response to different light treatments in octoploid strawberry plants are still unclear. In this study, the landscape of chromatin accessibility of octoploid strawberry under red (R) and yellow–green (YG) light conditions was analyzed by the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Through bioinformatics and Venn diagram analyses, a total of 1456 and 1854 group-specific genes (GSGs) were screened in the R and YG groups, respectively. By using RNA sequencing (RNA-seq), 440 differentially expressed genes (DEGs) were identified. Among these genes, 194 were upregulated under red light treatment. Through joint analysis of ATAC-seq and RNA-seq data, three red group-specific genes with increased expression were identified, namely, FaTIP1, FaQKY and FaLBD1. Through gene expression and transient transformation analyses of strawberry fruit, we further demonstrated that FaTIP1 can respond to red light induction and promote the ripening process of strawberry fruit. Our results provide a reference for the study of chromatin accessibility in octoploid strawberry and reveal new factors involved in the fruit's response to red light and the regulation of the ripening process of strawberry fruit. [ABSTRACT FROM AUTHOR]

The eye primordium of vertebrates initially forms exactly at the side of the head. Later, the eyeball architecture is tuned to see ahead with better visual acuity, but its molecular basis is unknown. The position of both eyes in the face alters in patients with holoprosencephaly due to Sonic hedgehog (Shh) mutations that disturb the development of the ventral midline of the neural tube. However, patient phenotypes vary extensively, and microforms without a brain anomaly relate instead to alternation of gene expression of the Shh signaling center in the facial primordia. We identified novel missense mutations of the Shh gene in two patients with a dislocated fovea, where the photoreceptor cells are condensed. Functional assays showed that Shh upregulates Patched and Gli and downregulates Pax6, and that Shh mutations alter these activities. Gain of function of Shh in a chick embryo retards retinal development and eyeball growth depending on the location of Shh expression, while loss of function of Shh promotes these features. We postulate that a signaling molecule like Shh that emanates from the face controls the extent of differentiation of the neural retina in a position-specific manner and that this may result in the formation of the fovea at the correct location. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) heterogeneity determines appropriate drug selection and affects efficacy of treatment. Effective therapy design can benefit from a combination of drugs directed against a specific type of BC with compounds that modulate components of crucial cellular regulatory systems, including the ubiquitin-proteasome system (UPS), which is responsible for the maintenance of protein homeostasis. Here, we revealed mutual influence and a correlation between the proteasome pool heterogeneity and the intratumoral expression of markers determining the BC subtype. Obtained results facilitate the development of novel BC subtype-specific therapy. Background: Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level of Ki67, HER-2, estrogen and progesterone receptors. Relationships between the presence of specific proteasome forms and proteins that determine the BC subtype remain unclear. Here, using gene expression data in 19,145 tumor samples from 144 datasets and tissues from 159 patients with different subtypes of BC, we investigated the association between the activity and expression of proteasomes and levels of BC subtype markers. Methods: Bioinformatic analysis of proteasome subunit (PSMB1-10) gene expression in BC was performed. Proteasome heterogeneity in BC cell lines was investigated by qPCR. By Western blotting, proteasome composition was assessed in cells and patient tissue lysates. Proteasome activities were studied using fluorogenic substrates. BC molecular subtypes were determined by immunohistochemistry. Results: BC subtypes demonstrate differing proteasome subunit expression pattern and strong PSMB8-10 co-correlation in tumors. A significant increase in chymotrypsin- and caspase-like proteasome activities in BC compared to adjacent tissues was revealed. The subunit composition of proteasomes in tumor tissues of BC subtypes varied. Regression analysis demonstrated a positive correlation between proteasome activities and the expression of Ki67, estrogen receptors and progesterone receptors. Conclusion: BC subtypes demonstrate differences within the proteasome pool. Correlations between the proteasome activity, hormone receptors and Ki67 indicate possible mutual influence. Obtained results facilitate development of novel drug combinations for BC therapy. [ABSTRACT FROM AUTHOR]

In the tissue regeneration field, stem cell transplantation represents a promising therapeutic strategy. To favor their implantation, proliferation and differentiation need to be controlled. Several studies have demonstrated that stem cell fate can be controlled by applying continuous electric field stimulation. This study aims to characterize the effect of a specific microsecond electric pulse stimulation (bipolar pulses of 100 µs + 100 µs, delivered for 30 min at an intensity of 250 V/cm) to induce an increase in cell proliferation on mesenchymal stem cells (MSCs) and induced neural stem cells (iNSCs). The effect was evaluated in terms of (i) cell counting, (ii) cell cycle, (iii) gene expression, and (iv) apoptosis. The results show that 24 h after the stimulation, cell proliferation, cell cycle, and apoptosis are not affected, but variation in the expression of specific genes involved in these processes is observed. These results led us to investigate cell proliferation until 72 h from the stimulation, observing an increase in the iNSCs number at this time point. The main outcome of this study is that the microsecond electric pulses can modulate stem cell proliferation. [ABSTRACT FROM AUTHOR]

DNA methylation is an essential epigenetic modification that plays a crucial role in regulating gene expression and maintaining genomic stability. With the advancement in sequencing technology, methylation studies have provided valuable insights into the diagnosis of rare diseases through the various identification of episignatures, epivariation, epioutliers, and allele-specific methylation. However, current methylation studies are not without limitations. This mini-review explores the current understanding of DNA methylation in rare diseases, highlighting the key mechanisms and diagnostic potential, and emphasizing the need for advanced methodologies and integrative approaches to enhance the understanding of disease progression and design more personable treatment for patients, given the nature of rare diseases. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the most prevalent forms of cancer globally, and has recently become the leading cause of cancer-related mortality in women. BC is a heterogeneous disease comprising various histopathological and molecular subtypes with differing levels of malignancy, and each patient has an individual prognosis. Etiology and pathogenesis are complex and involve a considerable number of genetic alterations and dozens of alterations in non-coding RNA expression. Non-coding RNAs are part of an abundant family of single-stranded RNA molecules acting as key regulators in DNA replication, mRNA processing and translation, cell differentiation, growth, and overall genomic stability. In the context of breast cancer, non-coding RNAs are involved in cell cycle control and tumor cell migration and invasion, as well as treatment resistance. Alterations in non-coding RNA expression may contribute to the development and progression of breast cancer, making them promising biomarkers and targets for novel therapeutic approaches. Currently, the use of non-coding RNAs has not yet been applied to routine practice; however, their potential has been very well studied. The present review is a literature overview of current knowledge and its objective is to delineate the function of diverse classes of non-coding RNAs in breast cancer, with a particular emphasis on their potential utility as diagnostic and prognostic markers or as therapeutic targets and tools. [ABSTRACT FROM AUTHOR]

The widespread and inappropriate use of antibiotics, for therapeutic and prophylactic purposes, has contributed to a global crisis of rapidly increasing antimicrobial resistance of microorganisms. This resistance is often associated with elevated mutagenesis induced by the presence of antibiotics. Additionally, subinhibitory concentrations of antibiotics can trigger stress responses in bacteria, further exacerbating this problem. In the present study, we investigated the effect of low doses of ciprofloxacin on the induction of the SOS response and the subsequent development of antibiotic resistance in Proteus spp. strains. Our findings revealed an increase in mutation frequencies within the studied strains, accompanied by a significant upregulation of recA expression. These observations were consistent across experiments involving two subinhibitory concentrations of ciprofloxacin. To establish mutation frequencies and assess gene expression changes, we utilized the RifS-to-RifR forward mutagenesis assay and RT-qPCR analysis, respectively. Furthermore, employing the microdilution method, we demonstrated that these changes could promote cross-resistance to multiple classes of antibiotics in Proteus spp. clinical strains. This, combined with the recurrent nature of Proteus-associated infections, poses a substantial risk of therapeutic failure. In conclusion, exposure to low doses of ciprofloxacin can significantly impact the susceptibility of Proteus bacilli, not only reducing their sensitivity to ciprofloxacin itself but also fostering resistance to other antibiotic classes. These findings underscore the importance of cautious antibiotic use and highlight the potential consequences of subinhibitory antibiotic exposure in clinical and environmental settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Chia seed oil is known as a powerhouse source of omega-3 (ω3) fatty acids, is rich in therapeutic bioactive components and natural antioxidants, and shows antimicrobial, anti-inflammatory, and heath-promoting properties in animals. The current research portrays the advantages of chia seed oil supplementation to address the unsustainable usage of fish oil in aquafeeds as well as to promote immunonutrition in tropical freshwater fish. The physiological and molecular responses tested through various endpoints depicted enhanced performance at the lowest level of CSO supplementation. However, higher dosages of dietary CSO supplementation at 2% and 3% led to a remarkable decline in haemato-immunological and biochemical responses. The results of the current study suggest the supplementation of chia seed oil at 1% to potentially improve the health performance and immunity of L. rohita fingerlings, whereas higher levels of CSO incorporation induced metabolic stress and immuno-suppression. The present investigation attempts to evaluate the impact of the dietary inclusion of chia (Salvia hispanica) seed oil (CSO) on the indices of haemato-immunology, metabolic enzymes, and expression of immune-responsive cytokine genes in Labeo rohita (rohu) fingerlings. The responses were observed in a 60-day feeding trial, set up with a total of 180 rohu fingerlings (19.74 ± 0.33 g) randomly allocated to four treatment groups with three replicates each. The groups were fed with a basal diet incorporated with 0%, 1.0%, 2.0%, and 3.0% CSO, denoted as control, CSO (1), CSO (2), and CSO (3), respectively. Significant (p < 0.05) augmentation of hematological indices such as total protein and globulin levels was observed in the group fed a 1.0% CSO-supplemented diet. Serum glucose, cholesterol, triglycerides, and complement reactive protein levels declined, whereas marker anti-oxidative enzymes (SOD, CAT, and GST) and protein metabolic enzymes (ALT and AST) increased (p < 0.05) in the lowest CSO-supplemented group. A significant upregulation of inflammatory cytokine viz. IL-1β, IFN-γ, TNF-α, and TLR22 alongside downregulation of IL-10 was noted in various tissues. The results support the inclusion of 1.0% CSO as a prospective dietary vegan substitute to fish oil in rohu aquaculture. [ABSTRACT FROM AUTHOR]

Little brown bats (Myotis lucifugus) cluster in hibernacula sites over winter, in which they use metabolic rate depression (MRD) to facilitate entrance and exit of hibernation. This study used small RNA sequencing and bioinformatic analyses to identify differentially regulated microRNAs (miRNAs) and to predict their downstream effects on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms in the skeletal muscle of torpid M. lucifugus as compared to euthermic controls. We observed a subset of ten miRNAs whose expression changed during hibernation, with predicted functional roles linked to cell cycle processes, downregulation of protein degradation via ubiquitin-mediated proteolysis, downregulation of signaling pathways, including MAPK, p53, mTOR, and TGFβ, and downregulation of cytoskeletal and vesicle trafficking terms. Taken together, our results indicate miRNA regulation corresponding to both widely utilized MRD survival strategies, as well as more hibernation- and tissue-specific roles in M. lucifugus, including skeletal muscle atrophy resistance via myostatin inhibition and insulin signaling suppression. [ABSTRACT FROM AUTHOR]

Simple Summary: The rabbit (Oryctolagus cuniculus), unlike primarily nocturnal rodents, exhibits flexible daily rhythms in its physiology and behavior, allowing it to adapt to nocturnal, diurnal or crepuscular conditions. These daily rhythms are regulated by a biological clock, a group of cells at the base of the brain. Ambient light is the main synchronizing signal of this clock, and through different pathways, time-related cues are communicated to other organs. There is a group of clock genes expressed at molecular level in every cell that contribute to modulating the daily rhythms throughout the body, and the endocrine system links the biological clock with the rest of the body. This study demonstrates how the absence of testicular hormones affects the expression of a clock protein and alters the daily pattern of locomotor activity, suggesting a clear endocrine effect on the biological clock and behavior. Our findings may relate to the seasonal reproductive behavior observed in this species. The suprachiasmatic nucleus (SCN) is the master regulator of the circadian system, modulating the daily timing of physiological and behavioral processes in mammals. While SCN synchronization is primarily driven by environmental light signals, sex hormones, particularly androgens, have a crucial role in regulating behavioral and reproductive processes to align with daily or seasonal cycles. SCN cell populations express receptors for sex steroid hormones, contributing to circadian synchronization mechanisms. Specifically, the activation of androgen receptors in the SCN has been shown to modulate clock gene expression and influence circadian rhythms. Rabbits, widely used in experimental research, exhibit unique behavioral patterns, including plasticity in circadian typology and seasonal variations in testosterone secretion. In this study, we explored, in male rabbits, the effect of castration on the daily pattern of locomotor activity and the expression of the clock protein PERIOD 1 (PER1) in the SCN. Our results show that castration significantly reduces daily locomotor activity and PER1 expression in the SCN. Moreover, a 4 h delay in the acrophase of PER1 expression was observed. We conclude that androgens have an important role in SCN synchronization mechanisms, contributing to the organization of physiological and behavioral events in this species. [ABSTRACT FROM AUTHOR]

Gene therapy is a promising approach to the treatment of various inherited diseases, but its development is complicated by a number of limitations of the natural promoters used. The currently used strong ubiquitous natural promoters do not allow for the specificity of expression, while natural tissue-specific promoters have lowactivity. These limitations of natural promoters can be addressed by creating new synthetic promoters that achieve high levels of tissue-specific target gene expression. This review discusses recent advances in the development of synthetic promoters that provide a more precise regulation of gene expression. Approaches to the design of synthetic promoters are reviewed, including manual design and bioinformatic methods using machine learning. Examples of successful applications of synthetic promoters in the therapy of hereditary diseases and cancer are presented, as well as prospects for their clinical use. [ABSTRACT FROM AUTHOR]

Drought stress is one of the main factors limiting the high yield and quality of potatoes. Arabinogalactan proteins (AGPs) are an important class of glycoproteins widely present in the cell walls, plasma membranes, and extracellular matrices of higher plants. Among them, fasciclin-like arabinogalactan proteins (FLAs) are involved in plant development, stress responses, and hormone signal regulation. However, little is known about the FLAs gene in potatoes. Based on transcriptome sequencing data, this study screened a drought stress-related candidate FLA gene (StFLA4) through bioinformatics and expression analysis in potatoes. qRT-PCR analysis showed that StFLA4 was induced by drought stress, and its expression decreased with the extension of stress time. Moreover, the relative expression level of StFLA4 in the drought-resistant variety "Kexin 1" was lower than in the drought-sensitive variety "Atlantic". The StFLA4 protein was located in the cell membrane and interacted with nineteen proteins, mainly related to response to environmental stimulus, cellular response to abiotic stimulus, and cell maturation. After heterologous overexpression of StFLA4 in tobacco, the transgenic plants showed more withered leaves than the wild-type tobacco under drought stress. During the drought stress period, the expression level of StFLA4 in the transgenic plants significantly decreased, and the activity of SOD and POD was significantly lower than that of WT. However, the MDA content was higher than that of WT. These results indicated that StFLA4 negatively regulates the response to drought stress. In addition, in the germination test of potato "Variety V7" tubers, it was found that the variation tendency of StFLA4 expression was along with the concentration of arabinogalactan proteins, and it may participate in the regulation of potato tuber germination. This study lays the foundation for elucidating the function and expression pattern of StFLA4 response to drought stress and tuber germination in potatoes. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) are widely used to infer the genetic basis of traits in organisms; however, selecting appropriate thresholds for analysis remains a significant challenge. In this study, we introduce the Sequential SNP Prioritization Algorithm (SSPA) to investigate the genetic underpinnings of two key phenotypes in Sorghum bicolor: maximum canopy height and maximum growth rate. Using a subset of the Sorghum Bioenergy Association Panel cultivated at the Maricopa Agricultural Center in Arizona, we performed GWAS with specific permissive-filtered thresholds to identify genetic markers associated with these traits, enabling the identification of a broader range of explanatory candidate genes. Building on this, our proposed method employed a feature engineering approach leveraging statistical correlation coefficients to unravel patterns between phenotypic similarity and genetic proximity across 274 accessions. This approach helps prioritize Single Nucleotide Polymorphisms (SNPs) that are likely to be associated with the studied phenotype. Additionally, we conducted a complementary analysis to evaluate the impact of SSPA by including all variants (SNPs) as inputs, without applying GWAS. Empirical evidence, including ontology-based gene function, spatial and temporal expression, and similarity to known homologs demonstrates that SSPA effectively prioritizes SNPs and genes influencing the phenotype of interest, providing valuable insights for functional genetics research. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are non-coding, single-stranded RNA molecules that regulate gene expression post-transcriptionally. Potato, an essential crop for food and fodder, experiences reduced quality and yield under shading. Although miRNAs have known roles in various plants, their regulatory mechanisms in potato shade avoidance remain unexplored. To investigate this, we constructed nine small RNA libraries from potato samples at 0, 5, and 10 days post-shade treatment. High-throughput sequencing identified 525 miRNAs (307 known and 218 novel) from 99 families, and 166 differentially expressed miRNAs (DEMs) were detected. qRT-PCR verified 10 DEMs, confirming sequencing reliability. Using TargetFinder, we predicted 4320 target genes of DEMs, which were enriched in plant–pathogen interaction and hormone signal transduction pathways, among others. These findings indicate that miRNAs may play key regulatory roles in potato shade avoidance by targeting specific genes, providing valuable insights for future functional studies and potential yield enhancement. [ABSTRACT FROM AUTHOR]

Testicular cancer is the most common cancer among young adult men and has favorable outcomes, with survival rates approaching 99% and over 80% for those with early and advanced stage disease, respectively. Biomarkers play a critical role in the diagnosis, pre-treatment risk stratification, surveillance, and assessment of post-treatment disease response in these men. Traditional serum tumor markers (STMs), which include alpha fetoprotein (AFP), beta subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are limited by low sensitivity (approximately 50%) during initial diagnosis; false-positive elevations as a result of other benign and malignant conditions; and negative levels in low-stage disease and in certain histologies such as teratoma and seminoma. As a result, novel biomarkers with potentially better performance characteristics, including microRNA (miRNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs), are being investigated. MicroRNAs are small noncoding RNA involved in transcription and translation and regulate the expression of almost one-third of human genes that regulate the cell cycle, differentiation, proliferation, and apoptosis. In germ cell tumor (GCT) patients, miR371a-3p has been identified as a promising biomarker with sensitivity and specificity of approximately 90–92% and 84–86%, respectively. The use of this new biomarker could aid in several clinical scenarios, such as predicting the presence of micrometastases in chemotherapy-naïve patients with clinical stage I–II disease, thereby guiding decisions on treatment versus surveillance and predicting the presence of viable GCT in patients with residual disease post chemotherapy. Clinical trials are ongoing to validate the use of miRNA 371 as a biomarker and to define its performance characteristics. Though promising, miRNAs are limited by their inability to detect teratoma. ctDNA and CTCs are two other emerging biomarkers, though further studies are needed to clarify their role in managing patients with GCT. [ABSTRACT FROM AUTHOR]

Background: 20-Hydroxyecdysone (20E) is the most ubiquitous ecdysteroid (Ecd) and plays critical roles during the life cycle of arthropods. To elucidate the metabolism pathway of 20E in the economically important species, Scylla paramamosain, we conducted a comprehensive exploration of the genes involved in the 20E metabolism pathway. Methods: A comprehensive exploration of genes involved in the 20E metabolism pathway was conducted, including gene annotation, local blast using the Drosophila ortholog as query, and TreeFam ortholog genes identification. Bioinformatics and expression profiling of the identified genes were performed to assess their roles in the 20E metabolism of green mud crabs. Results: This experiment indicated that, except for CYP306a1 and CYP314a1, all other ortholog genes involved in the Drosophila 20E metabolism can be found in the mud crab, suggesting that the function of these two genes might be replaced by other CYP genes or the "active" Ecd in mud crabs was not the 20E. All genes had the typical features of each gene family, clustered with the specific clade in the phylogenetic trees. In addition, all the identified genes had the highest expression level in the Y-organ, and sex-biased gene expression was observed in these genes. Conclusions: This study provided some valuable insights into the metabolism and diversity of ecdysteroids in crustaceans. [ABSTRACT FROM AUTHOR]

Background/objectives: Nucleolin is a major component of the nucleolus and is involved in various aspects of ribosome biogenesis. However, it is also implicated in non-nucleolar functions such as cell cycle regulation and proliferation, linking it to various pathologic processes. The aim of this study was to use differential gene expression analysis and Weighted Gene Co-expression Network analysis (WGCNA) to identify nucleolin-related regulatory pathways and possible key genes as novel therapeutic targets for cancer, viral infections and other diseases. Methods: We used two different siRNAs to downregulate the expression of nucleolin in a human hepatoblastoma (HepG2) cell line. We carried out RNA-sequencing (RNA-Seq), performed enrichment analysis of the pathways of the differentially expressed genes (DEGs) and identified protein–protein interaction (PPI) networks. Results: Both siRNAs showed high knockdown efficiency in HepG2 cells, resulting in the disruption of the nucleolar architecture and the downregulation of rRNA gene expression, both downstream hallmarks of a loss of nucleolin function. RNA-Seq identified 44 robust DEGs in both siRNA cell models. The enrichment analysis of the pathways of the downregulated genes confirmed the essential role of nucleolin in DNA replication and cell cycle processes. In addition, we identified seven hub genes linked to NCL: MCM6, MCM3, FEN1, MYBL2, MSH6, CDC6 and RBM14; all are known to be implicated in DNA replication, cell cycle progression and oncogenesis. Conclusions: Our findings demonstrate the functional consequences of nucleolin depletion in HepG2 and confirm the importance of nucleolin in DNA replication and cell cycle processes. These data will further enhance our understanding of the molecular and pathologic mechanisms of nucleolin and provide new therapeutic perspectives in disease. [ABSTRACT FROM AUTHOR]

Common oat (Avena sativa L.) is one of the important minor grain crops in China, and drought stress severely affects its yield and quality. To investigate the drought resistance characteristics of oat seedlings, this study used Baiyan 2, an oat cultivar at the three-leaf stage, as the experimental material. Drought stress was simulated using polyethylene glycol (PEG) to treat the seedlings. The photosynthetic parameters and physicochemical indices of the treatment groups at 6 h and 12 h were measured and compared with the control group at 0 h. The results showed that drought stress did not significantly change chlorophyll content, but it significantly reduced net photosynthetic rate and other photosynthetic parameters while significantly increasing proline content. Transcriptome analysis was conducted using seedlings from both the control and treatment groups, comparing the two treatment groups with the control group using Tbtool software (v2.136). This analysis identified 344 differentially expressed genes. Enrichment analysis of these differentially expressed genes revealed significant enrichment in physiological pathways such as photosynthesis and ion transport. Ten differentially expressed genes related to the physiological process of photosynthetic carbon assimilation were identified, all of which were downregulated. Additionally, seven differentially expressed genes were related to ion transport. Through gene co-expression analysis combined with promoter region structure analysis, 11 transcription factors (from MYB, AP2/ERF, C2C2-dof) were found to regulate the expression of 10 genes related to photosynthetic carbon assimilation. Additionally, five transcription factors regulate the expression of two malate transporter protein-related genes (from LOB, zf-HD, C2C2-Dof, etc.), five transcription factors regulate the expression of two metal ion transporter protein-related genes (from MYB, zf-HD, C2C2-Dof), five transcription factors regulate the expression of two chloride channel protein-related genes (from MYB, bZIP, AP2/ERF), and two transcription factors regulate the expression of one Annexin-related gene (from NAC, MYB). This study provides a theoretical foundation for further research on the molecular regulation of guard cells and offers a molecular basis for enhancing drought resistance in oats. [ABSTRACT FROM AUTHOR]

Objective: The poultry industry is significantly impacted by viral infections, particularly Newcastle Disease Virus (NDV), which leads to substantial economic losses. It is essential to comprehend how the sequence of development affects biological pathways and how early exposure to infections might affect immune responses. Methods: This study employed transcriptome analysis to investigate host–pathogen interactions by analyzing gene expression changes in NDV-infected chicken embryos' lungs. Result: RNA-Seq reads were aligned with the chicken reference genome (Galgal7), revealing 594 differentially expressed genes: 264 upregulated and 330 downregulated. The most overexpressed genes, with logFC between 8.15 and 8.75, included C8A, FGG, PIT54, FETUB, APOC3, and FGA. Notably, downregulated genes included BPIFB3 (−4.46 logFC) and TRIM39.1 (−4.26 logFC). The analysis also identified 29 novel transcripts and 20 lncRNAs that were upregulated. Gene Ontology and KEGG pathways' analyses revealed significant alterations in gene expression related to immune function, metabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. Key metabolic genes, such as ALDOB (3.27 logFC), PRPS2 (2.66 logFC), and XDH (2.15 logFC), exhibited altered expression patterns, while DCK2 (−1.99 logFC) and TK1 (−2.11 logFC) were also affected. Several immune-related genes showed significant upregulation in infected lung samples, including ALB (6.15 logFC), TLR4 (1.86 logFC), TLR2 (2.79 logFC), and interleukin receptors, such as IL1R2 (3.15 logFC) and IL22RA2 (1.37 logFC). Conversely, genes such as CXCR4 (−1.49 logFC), CXCL14 (−2.57 logFC), GATA3 (−1.51 logFC), and IL17REL (−2.93 logFC) were downregulated. The higher expression of HSP genes underscores their vital role in immune responses. Conclusion: Comprehension of these genes' interactions is essential for regulating viral replication and immune responses during infections, potentially aiding in the identification of candidate genes for poultry breed improvement amidst NDV challenges. [ABSTRACT FROM AUTHOR]

Simple Summary: The nuclear protein lens epithelium derived growth factor of 75 kD (LEDGF/p75) has recently attracted considerable attention in the field of cancer research because of its high abundance in cancer cells and its role in promoting tumor aggressive properties. LEDGF/p75 is activated in cancer cells by agents that trigger cellular stress such as chemotherapeutic drugs. This protein has two major structural features, the PWWP domain and the IBD domain. These domains allow LEDGF/p75 to play important roles in cancer cells, including repairing damage to DNA, regulating the processing of messenger RNA, and binding to other nuclear proteins that are necessary to activate cancer-related genes involved in promoting cancer aggressiveness and resistance to therapy. This article discusses LEDGF/p75's role in cancer and therapy resistance, and its potential as a therapeutic target for developing new combinatorial cancer treatments. The lens epithelium derived growth factor of 75 kD (LEDGF/p75) is a transcription co-activator and epigenetic reader that has emerged as a stress oncoprotein in multiple human cancers. Growing evidence indicates that it promotes tumor cell survival against certain therapeutic drugs. The amino (N)-terminal region of LEDGF/p75 contains a PWWP domain that reads methylated histone marks, critical for recognizing transcriptionally active chromatin sites. Its carboxyl (C)-terminus has an integrase binding domain (IBD) that serves as the binding site for the HIV-1 integrase and multiple oncogenic transcription factors. Acting as hubs for protein-protein interactions, both domains facilitate the tethering of oncogenic transcription factors and regulators to active chromatin to regulate mRNA splicing, promote DNA repair, and enhance the expression of stress and cancer-related genes that contribute to tumor cell aggressiveness and chemoresistance. This review summarizes our current knowledge of the emerging roles of LEDGF/p75 in cancer biology and therapy resistance and discusses its potential as a novel oncotherapeutic target in combinatorial treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Sinonasal carcinoma and olfactory neuroblastoma have very limited therapeutic options. The expression of the somatostatin receptor 2 (SSTR2) gene has been described in these patients, and the successful use of SSTR2-targeted treatments have been reported. This study investigates the association of SSTR2 expression with genomic features, immune biomarkers, and the tumor immune microenvironment in a cohort of patients with sinonasal malignancies. Olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), and sinonasal neuroendocrine carcinoma (SNEC) are rare malignancies arising from the sinonasal tract with limited therapeutic options. The expression of the somatostatin receptor 2 gene (SSTR2), which is expressed in other neuroendocrine neoplasms and is therapeutically actionable, has been reported in these tumors. Here, we analyzed SSTR2 gene expression and its associations with genomic features, established biomarkers predicting of immune response, and the tumor immune microenvironment in a cohort of ONB, SNUC, and SNEC tumor samples (26, 13, and 8 samples, respectively) from a real-world database. SSTR2 gene expression was high in neural-type ONB and low in basal-type ONB and in most of the SNUC and SNEC cases; there was no difference in expression between primary and metastatic tumors. The T cell-inflamed (TCI) score analysis classified 38.5% of SNUC cases as T cell-inflamed compared to only 3.9% of ONB and 0% of SNEC cases; 26.9% of ONB cases were classified as intermediate TCI; and SNEC had the lowest relative immune cell infiltration by deconvolution. In high SSTR2-expressing ONB, there was a higher proportion of infiltrating of Natural Killer cells and dendritic cells by deconvolution. Additionally, high SSTR2-expressing ONB was enriched for proliferation pathways, including E2F and Myc targets and G2M checkpoints. In conclusion, our findings delineate significant differences between these three types of sinonasal malignancies that were examined. In ONB, relative to SNUC and SNEC, the SSTR2 expression profile, combined with its immune profiles, indicates potential novel therapeutic strategies and combinations for this unmet clinical need. Conversely, the inflammatory microenvironment of SNUC may be targetable using immuno-oncologic therapies. [ABSTRACT FROM AUTHOR]

Bridging the gap between cortical morphometric remodeling and gene expression can help to clarify the effects of the selective brain accumulation of Amyloid- β (A β) and tau proteins occurring in the Alzheimer's disease (AD). To this aim, we derived morphometric similarity (MS) networks from 126 A β - and tau-positive (A β +/tau+) and 172 A β −/tau− subjects, and we investigated the association between group-wise regional MS differences and transcriptional correlates thanks to an imaging transcriptomics approach grounded in the Allen Human Brain Atlas (AHBA). The expressed gene with the highest correlation with MS alterations was BCHE, a gene related to A β homeostasis. In addition, notably, among the most promising results derived from the enrichment analysis, we found the immune response to be a biological process and astrocytes, microglia, and oligodendrocyte precursors for the cell types. In summary, by relating cortical MS and AHBA-derived transcriptomics, we were able to retrieve findings suggesting the biological mechanisms underlying the A β - and tau- induced cortical MS alterations in the AD continuum. [ABSTRACT FROM AUTHOR]

Autophagy is a process of self-degradation that enables the cell to survive when faced with starvation or stressful conditions. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, plays a critical role in maintaining a balance between cellular anabolism and catabolism. mTOR complex 1 (mTORC1) was unveiled as a master regulator of autophagy since inhibition of mTORC1 was required to initiate the autophagy process. Evidence has emerged in recent years to indicate that mTORC1 also directly regulates the subsequent steps of the autophagy process, including the nucleation, autophagosome elongation, autophagosome maturation and termination. By phosphorylating select protein targets of the autophagy core machinery and/or their regulators, mTORC1 can alter their functions, increase their proteasomal degradation or modulate their acetylation status, which is a key switch of the autophagy process. Moreover, it phosphorylates and alters the subcellular localization of transcription factors to suppress the expression of genes needed for autophagosome formation and lysosome biogenesis. The purpose of this review article is to critically analyze current literatures to provide an integrated view of how mTORC1 regulates various steps of the autophagy process. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH–GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways. [ABSTRACT FROM AUTHOR]

Activation of Wnt signaling induces Connexin43 (Cx43) expression via the transcriptional activity of β-catenin, and results in the enhanced accumulation of the Cx43 protein and the formation of gap junction channels. In response to Wnt signaling, β-catenin co-localizes with the Cx43 protein itself as part of a complex at the gap junction plaque. Work from several labs have also shown indirect evidence of this interaction via reciprocal co-immunoprecipitation. Our goal for the current study was to identify whether β-catenin directly interacts with Cx43, and if so, the location of that direct interaction. Identifying residues involved in direct protein–protein interaction is of importance when they are correlated to the phosphorylation of Cx43, as phosphorylation can modify the binding affinities of Cx43 regulatory protein partners. Therefore, combining the location of a protein partner interaction on Cx43 along with the phosphorylation pattern under different homeostatic and pathological conditions will be crucial information for any potential therapeutic intervention. Here, we identified that β-catenin directly interacts with the Cx43 carboxyl-terminal domain, and that this interaction would be inhibited by the Src phosphorylation of Cx43CT residues Y265 and Y313. [ABSTRACT FROM AUTHOR]

Cowpea (Vigna unguiculata (L.) Walp.) is an important legume cultivated mainly in regions with limited water availability across the African and American continents. Its productivity is significantly affected by environmental stresses. Thaumatin-like proteins (TLPs), which belong to the PR-5 (pathogenesis-related 5) protein family, are known to be responsive to both biotic and abiotic stresses. However, their role remains controversial, with some TLPs associated with plant defense (particularly against fungal infections) and others associated with abiotic stresses response. In this study, we evaluated the structural diversity and gene expression of TLPs in cowpea (VuTLPs) under different stress conditions, including biotic [mechanical injury followed by inoculation with Cowpea Aphid-borne Mosaic Virus (CABMV) or Cowpea Severe Mosaic Virus (CPSMV)] and abiotic (root dehydration). Genomic anchoring of VuTLPs revealed 34 loci encoding these proteins. Neighbor- joining analysis clustered the VuTLPs into three distinct groups. We identified 15 segmental duplication and 6 tandem duplication gene pairs, with the majority of VuTLP genes found to be under purifying selection. Promoter analysis associated VuTLPs with bHLH, Dof-type, and MYB- related transcription factors, supporting their diverse roles. Diversity in VuTLP function was also observed in their expression profiles under the studied stress conditions. Gene expression data showed that most VuTLPs are recruited within the first minutes after biotic stress imposition. For the root dehydration assay, the most transcripts were up-regulated 150 min post-stress. Moreover, the gene expression data suggested that VuTLPs exhibit functional specialization depending on the stress condition, highlighting their diverse roles and biotechnological potential. [ABSTRACT FROM AUTHOR]

Simple Summary: Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at identifying the molecular factors associated with disease relapse and investigating them as therapeutically exploitable targets. Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance. Background: Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at the identification of the molecular factors associated with disease relapse and their further investigation as therapeutically exploitable targets. Methods: Analyses were conducted on formalin-fixed paraffin-embedded tissues of the primary tumors of relapsed (cases) and not relapsed (controls) HER2+ BC patients treated with adjuvant trastuzumab. The nCounter Human Breast Cancer Panel 360 was used. Logistic regression and partitioning around medoids were employed to identify the genes associated with disease recurrence. Cytotoxicity experiments using trastuzumab-resistant cell lines and a network pharmacology approach were carried out to investigate drug efficacy. Results: A total of 52 patients (26 relapsed and 26 not relapsed) were analyzed. We found that a higher expression of HDAC6 was significantly associated with an increased risk of recurrence, with an adjusted OR of 3.20 (95% CI 1.38–9.91, p = 0.016). Then, we investigated the cytotoxic activity of the selective HDAC6 inhibitor Nexturastat A (NextA) on HER2+ cell lines, which were both sensitive and trastuzumab-resistant. A sub-cytotoxic concentration of NextA, combined with trastuzumab, showed a synergistic effect on BC cell lines. Finally, using a network pharmacology approach, we identified HSP90AA1 as the putative molecular candidate responsible for the synergism observed in vitro. Conclusions: Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the role of c-MYC in Chronic Lymphocytic Leukemia (CLL) and its impact on genetic instability and disease progression. As a key oncogene, c-MYC encodes a transcription factor involved in regulating cell cycle, growth, and apoptosis. We previously described CLL cases enriched with unmutated IGHV genes, MYC overexpression and with active rearrangement of the IGH immunoglobulin heavy chain (IGH) locus. The MYC overexpression seems to promote increased DNA damage, including double-strand breaks (DSBs), chromosomal translocations linked to repair errors during DNA repair. Highlighting c-MYC's dual role, this review try to show how MYC overexpression it not only driving cell proliferation but also contributes to genomic instability. This review examines the pivotal role of c-MYC in Chronic Lymphocytic Leukemia (CLL), focusing on how its overexpression leads to increased genetic instability, thereby accelerating disease progression. MYC, a major oncogene, encodes a transcription factor that regulates essential cellular processes, including cell cycle control, proliferation, and apoptosis. In CLL cases enriched with unmutated immunoglobulin heavy chain variable (IGHV) genes, MYC is significantly overexpressed and associated with active rearrangements in the IGH immunoglobulin heavy chain locus. This overexpression results in substantial DNA damage, including double-strand breaks, chromosomal translocations, and an increase in abnormal repair events. Consequently, c-MYC plays a dual role in CLL: it promotes aggressive cell proliferation while concurrently driving genomic instability through its involvement in genetic recombination. This dynamic contributes not only to CLL progression but also to the overall aggressiveness of the disease. Additionally, the review suggests that c-MYC's influence on genetic rearrangements makes it an attractive target for therapeutic strategies aimed at mitigating CLL malignancy. These findings underscore c-MYC's critical importance in advancing CLL progression, highlighting the need for further research to explore its potential as a target in future treatment approaches. [ABSTRACT FROM AUTHOR]

ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regulation of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which ALDH1A3 promotes malignant progression of glioblastoma remain elusive posing a challenge for rationalization of ALDH1A3 targeting in glioblastoma, and it is also unclear how ALDH1A3 regulates glioblastoma cells stemness. Usage of different models with diverse genetic backgrounds and often unknown degree of stemness is one possible reason for discrepant views on the role of ALDH1A3 in glioblastoma stem cells. This study clarifies ALDH1A3 impacts on glioblastoma stem cells by modelling ALDH1A3 expression in an otherwise invariable genetic background with consideration of the impacts of inherent plasticity and proliferative changes associated with transitions between cell states. Our main finding is that ALDH1A3 exerts cell-state dependent impact on proliferation of glioblastoma stem cells. We provide evidence that ALDH1A3 augments radiation-induced inhibition of self-renewal and promotes the proliferation of differentiated GSC progenies. Congruent effects ALDH1A3 and radiation on self-renewal and proliferation provides a framework for promoting glioblastoma growth under radiation treatment. [ABSTRACT FROM AUTHOR]

Multicellular organisms exhibit inherent cellular heterogeneity that cannot be captured by traditional high-throughput sequencing techniques, resulting in the unique cellular characteristics of individual cells being neglected. Single-cell transcriptome sequencing (scRNA-seq) technology can be used to determine the gene expression levels of each individual cell, facilitating the study of intercellular expression heterogeneity. This review provides a comprehensive overview of the development and applications of scRNA-seq technology in plant research. We highlight the significance of integrating single-cell multi-omics approaches to achieve a holistic understanding of plant systems. Additionally, we discuss the current challenges and future research directions for scRNA-seq technology in plant studies, aiming to offer valuable insights for its application across various plant species. [ABSTRACT FROM AUTHOR]

Background: Ammopiptanthus mongolicus is a rare temperate evergreen shrub with high tolerance to low temperature, and understanding the related gene expression regulatory network can help advance research on the mechanisms of plant tolerance to abiotic stress. Methods: Here, time-course transcriptome analysis was applied to investigate the gene expression network in A. mongolicus under low temperature stress. Results: A total of 12,606 differentially expressed genes (DEGs) were identified at four time-points during low temperature stress treatment, and multiple pathways, such as plant hormones, secondary metabolism, and cell membranes, were significantly enriched in the DEGs. Trend analysis found that the expression level of genes in cluster 19 continued to upregulate under low temperatures, and the genes in cluster 19 were significantly enriched in plant hormone signaling and secondary metabolic pathways. Based on the transcriptome data, the expression profiles of the genes in abscisic acid, salicylic acid, and flavonoid metabolic pathways were analyzed. It was found that biosynthesis of abscisic acid and flavonoids may play crucial roles in the response to low temperature stress. Furthermore, members of the phenylalanine ammonia-lyase (PAL) family in A. mongolicus were systematically identified and their structures and evolution were characterized. Analysis of cis-acting elements showed that the PAL genes in A. mongolicus were closely related to abiotic stress response. Expression pattern analysis showed that PAL genes responded to various environmental stresses, such as low temperature, supporting their involvement in the low temperature response in A. mongolicus. Conclusions: Our study provides important data for understanding the mechanisms of tolerance to low temperatures in A. mongolicus. [ABSTRACT FROM AUTHOR]

Background/Objectives: Adverse childhood experiences (ACEs) are potent drivers of psychopathology and neurological disorders, especially within minoritized populations. Nonetheless, we lack a coherent understanding of the neuronal mechanisms through which ACEs impact gene expression and, thereby, the development of psychopathology. Methods: This observational pilot study used a novel marker of neuronal functioning (brain-derived micro ribonucleic acids, or miRNAs) collected via saliva to explore the connection between ACEs and neuronal gene expression in 45 adolescents with a collectively high ACE exposure (26 males and 19 females of diverse races/ethnicities, with six cumulative ACEs on average). We aimed to determine the feasibility of using salivary microRNA for probing neuronal gene expression with the goal of identifying cellular processes and genetic pathways perturbed by childhood adversity. Results: A total of 274 miRNAs exhibited reliable salivary expression (raw counts > 10 in > 10% of samples). Fourteen (5.1%) were associated with cumulative ACE exposure (p < 0.05; r's ≥ 0.31). ACE exposure correlated negatively with miR-92b-3p, 145a-5p, 31-5p, and 3065-5p, and positively with miR-15b-5p, 30b-5p, 30c-5p, 30e-3p, 199a-3p, 223-3p, 338-3p, 338-5p, 542-3p, and 582-5p. Most relations remained significant after controlling for multiple comparisons and potential retrospective bias in ACE reporting for miRNAs with particularly strong relations (p < 0.03). We examined KEGG pathways targeted by miRNAs associated with total ACE scores. Results indicated putative miRNA targets over-represented 47 KEGG pathways (adjusted p < 0.05) involved in neuronal signaling, brain development, and neuroinflammation. Conclusions: Although preliminary and with a small sample, the findings represent a novel contribution to the understanding of how childhood adversity impacts neuronal gene expression via miRNA signaling. [ABSTRACT FROM AUTHOR]

Biofertilizers offer a sustainable method for improving rice growth and productivity, yet their effects on the interaction between plant growth, photosynthetic activity, and gene expression remain under-researched. This study examines how biofertilizer influences rice physiology, focusing on photosynthetic regulation and expression of chlorophyll-related genes. Eight fertilizer treatments were applied: control (CNT), biofertilizer (BF), deactivated biofertilizer (DABF), rice straw (RS), rice straw with biofertilizer (RS+BF), organic fertilizer (OF), organic fertilizer with biofertilizer (OF+BF), and inorganic fertilizer (IOF). Plant height, tiller number, SPAD, NDVI, chlorophyll content, and photosynthesis rates were measured, while gene expression analysis was conducted using RT-qPCR. The OF+BF treatment produced the most significant results, leading to a 31% increase in plant height, a 135% increase in tiller number, and a 42% increase in chlorophyll content (SPAD values) compared to the control. Additionally, OF+BF enhanced photosynthetic efficiency by 74%, with the highest net photosynthetic rate of 48.23 μmol CO2 m−2 s−1. Gene expression analysis revealed that OF+BF upregulated key photosynthesis-related genes, such as OsChlD and OsCHLM, showing a 70% and 90% increase in expression. These findings highlight the potential of integrating biofertilizers with organic fertilizers to sustainably boost rice growth and productivity, contributing to global food security and climate change mitigation. [ABSTRACT FROM AUTHOR]

Normotensive and hypertensive organisms respond differently to stress factors; however, the features of the central molecular genetic mechanisms underlying the reaction of the hypertensive organism to stress have not been fully established. In this study, we examined the transcriptome profiles of the hypothalamus of hypertensive ISIAH rats, modeling a stress-sensitive form of arterial hypertension, and normotensive WAG rats at rest and after exposure to a single short-term restraint stress. It was shown that oxidative phosphorylation is the most significantly enriched process among metabolic changes in the hypothalamus of rats of both strains when exposed to a single short-term restraint stress. The analysis revealed DEGs representing both a common response to oxidative stress for both rat strains and a strain-specific response to oxidative stress for hypertensive ISIAH rats. Among the genes of the common response to oxidative stress, the most significant changes in the transcription level were observed in Nos1, Ppargc1a, Abcc1, Srxn1, Cryab, Hspb1, and Fosl1, among which Abcc1 and Nos1 are associated with hypertension, and Fosl1 and Ppargc1a encode transcription factors. The response to oxidative stress specific to hypertensive rats is associated with the activation of the Fos gene. The DEG's promoter region enrichment analysis allowed us to hypothesize that the response to oxidative stress may be mediated by the participation of the transcription factor CREB1 (Cyclic AMP-responsive element-binding protein 1) and the glucocorticoid receptor (NR3C1) under restraint stress in the hypothalamus of both rat strains. The results of the study revealed common and strain-specific features in the molecular mechanisms associated with oxidative phosphorylation and oxidative stress response in the hypothalamus of hypertensive ISIAH and normotensive WAG rats following a single short-term restraint stress. The obtained results expand the understanding of the most significant molecular targets for further research aimed at developing new therapeutic strategies for the prevention of the consequences of acute emotional stress, taking into account the hypertensive state of the patient. [ABSTRACT FROM AUTHOR]

The use of plant growth-promoting rhizobacteria presents a promising addition to conventional mineral fertilizer use and an alternative strategy for sustainable agricultural crop production. However, genotypic variations in the plant host may result in variability of the beneficial effects from these plant–microbe interactions. This study examined growth promotion effects of commercial vegetable crop cultivars of tomato, cucumber and broccoli following application with five rhizosphere bacteria. Biochemical assays revealed that the bacterial strains used possess several nutrient acquisition traits that benefit plants, including nitrogen fixation, phosphate solubilization, biofilm formation, and indole-3-acetic acid (IAA) production. However, different host cultivars displayed genotype-specific responses from the inoculations, resulting in significant (p < 0.05) plant growth promotion in some cultivars but insignificant (p > 0.05) or no growth promotion in others. Gene expression profiling in tomato cultivars revealed that these cultivar-specific phenotypes are reflected in differential expressions of defense and nutrient acquisition genes, suggesting that plants can be categorized into "microbe-friendly" cultivars (with little or no defense responses against beneficial microbes) and "microbe-hostile" cultivars (with strong defense responses). These results validate the notion that "microbe-friendly" (positive interaction with rhizosphere microbes) should be considered an important trait in breeding programs when developing new cultivars which could result in improved crop yields. [ABSTRACT FROM AUTHOR]

Microalgae have demonstrated biostimulant potential owing to their ability to produce various plant growth-promoting substances, such as amino acids, phytohormones, polysaccharides, and vitamins. Most previous studies have primarily focused on the effects of microalgal biostimulants on plant growth. While biomass extracts are commonly used as biostimulants, research on the use of culture supernatant, a byproduct of microalgal culture, is scarce. In this study, we aimed to evaluate the potential of Chlorella vulgaris culture as a biostimulant and assess its effects on the growth and drought tolerance of Arabidopsis thaliana, addressing the gap in current knowledge. Our results demonstrated that the Chlorella cell-free supernatant (CFS) significantly enhanced root growth and shoot development in both seedlings and mature Arabidopsis plants, suggesting the presence of specific growth-promoting compounds in CFS. Notably, CFS appeared to improve drought tolerance in Arabidopsis plants by increasing glucosinolate biosynthesis, inducing stomatal closure, and reducing water loss. Gene expression analysis revealed considerable changes in the expression of drought-responsive genes, such as IAA5, which is involved in auxin signaling, as well as glucosinolate biosynthetic genes, including WRKY63, MYB28, and MYB29. Overall, C. vulgaris culture-derived CFS could serve as a biostimulant alternative to chemical products, enhancing plant growth and drought tolerance. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein has been shown to promote tumor progression, its role in the development of cervical cancer remains unclear. We find that its level is higher in cervical cancer tissues than in normal cervical tissues. And it promotes metastasis in HeLa cell lines by facilitating the epithelial-mesenchymal transition process, thereby enhancing the migration of HeLa cells in vivo. Our research might provide a new marker for predicting the development of cervical cancer. Background: Cervical cancer is the fourth most common cancer among women worldwide. The zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein specifically binds to GC-rich DNA sequences and regulates gene expression, and it has been shown to promote tumor progression. In this study, we aim to investigate the function and molecular mechanism of ZNF281 in uterine cervical carcinoma. Methods: We conducted immunohistochemistry and Western blot assays to determine the expression of ZNF281 in eight human cervical cancer tissues. And, xenograft experiments involving the injection of HeLa cells into nude mice was used to determine the function of ZNF281 on proliferation. Transwell assays were used to detect the migration and invasion of HeLa cells after indicated that ZNF281 overexpression. Results: Our results indicated that ZNF281 protein levels were higher in cervical cancer tissues compared to normal cervical tissues. Additionally, ZNF281 was expressed in human cervical carcinoma cell lines, including HeLa, SiHa, C-33 A, CaSki, and HT-3, and is localized in both the cell nucleus and cytoplasm. ZNF281 overexpression did not influence HeLa cell proliferation or tumor size in situ. Moreover, nude mice injected with ZNF281-overexpressing cell lines developed more tumor lesions in the lungs compared to those injected with control cell lines. Conclusions: These findings suggest that ZNF281 is associated with tumor metastasis without affecting cell proliferation, both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) is a deadly form of cancer, affecting areas like the mouth, throat, and larynx. This review explores the complex molecular pathways involved in HNSCC development and progression, focusing on the role of microRNAs (miRNAs)—small molecules that regulate gene expression. We aim to provide a comprehensive overview of how miRNAs influence HNSCC, their potential as diagnostic and prognostic markers, and their use in developing new targeted therapies. We also discuss promising nanotechnology-based approaches for delivering miRNA therapies more effectively. By synthesizing the current knowledge on miRNAs in HNSCC, this research may help identify new biomarkers for early detection and prognosis, as well as novel therapeutic targets. Ultimately, these insights could lead to improved personalized treatments and better outcomes for HNSCC patients. This paper presents a comprehensive comparative analysis of biomarkers for head and neck cancer (HNC), a prevalent but molecularly diverse malignancy. We detail the roles of key proteins and genes in tumourigenesis and progression, emphasizing their diagnostic, prognostic, and therapeutic relevance. Our bioinformatic validation reveals crucial genes such as AURKA, HMGA2, MMP1, PLAU, and SERPINE1, along with microRNAs (miRNA), linked to HNC progression. OncomiRs, including hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-196a-5p, and hsa-miR-200c-3p, drive tumourigenesis, while tumour-suppressive miRNAs like hsa-miR-375 and hsa-miR-145-5p inhibit it. Notably, hsa-miR-155-3p correlates with survival outcomes in addition to the genes RAI14, S1PR5, OSBPL10, and METTL6, highlighting its prognostic potential. Future directions should focus on leveraging precision medicine, novel therapeutics, and AI integration to advance personalized treatment strategies to optimize patient outcomes in HNC care. [ABSTRACT FROM AUTHOR]

Post-transcriptional gene regulation mediated by microRNAs (miRNAs) relies on sequence complementarity between the miRNA seed site and the target gene transcript(s). This complementarity can completely inhibit or reduce translation into protein. We hypothesized that viruses employ sequence complementarity/similarity with host miRNAs to inhibit or increase the miRNA-mediated regulation of host gene expression specifically during viral infection(s). In this study, we focus on Orthoavulavirus javaense (OAVJ), the causative of Newcastle disease, a poultry disease with significant economic impact. A computational analysis of OAVJ genomes from low-virulence (lentogenic) versus virulent (velogenic) viruses was carried out to identify viral signature motifs that potentially either mimic or complement host miRNA seed sequences. Data show that OAVJ genomes harbor viral seed mimics (vSMs) or viral seed sponges (vSSs) and can mimic host miRNAs or inhibit their regulation of host genes, disrupting cellular pathways. Our analyses showed that velogens encode a statistically significant higher number of vSMs and a lower number of vSSs relative to lentogens. The number of vSMs or vSSs did not correlate with gene length. The analysis of the secondary structures flanking these vSMs and vSSs showed structural features common to miRNA precursors. The inhibition or upregulation of vSS-miR-27b-5p altered P gene expression in a sequence-dependent manner. These data demonstrate that viral transcripts can interact with host miRNAs to alter the outcomes of infection. [ABSTRACT FROM AUTHOR]

The in vitro generation of spermatogonial stem cells (SSCs) from embryonic stem cells (ESCs) offers a viable approach for addressing male infertility. A multitude of molecules participate in this intricate process, which requires additional elucidation. Despite the decline in SSCs in aged testes, SSCs are deemed immortal since they can multiply for three years with repeated transplantation. Nonetheless, the examination of aging is challenging due to the limited quantity and absence of precise indicators. Using a microarray, we assessed genome-wide transcripts (about 55,000 transcripts) of fibroblasts and SSCs. The WGCNA approach was then used to look for SSC-specific transcription factors (TFs) and hub SSC-specific genes based on ATAC-seq, DNase-seq, RNA-seq, and microarray data from the GEO databases as well as gene expression data (RNA-seq and microarray data). The microarray analysis of three human cases with different SSCs revealed that 6 genes were upregulated, and the expression of 23 genes was downregulated compared to the normal case in relation to aging genes. To reach these results, online assessments of Enrich Shiny GO, STRING, and Cytoscape were used to forecast the molecular and functional connections of proteins before identifying the master routes. The biological process and molecular function keywords of cell–matrix adhesion, telomerase activity, and telomere cap complex were shown to be significantly altered in upregulated differentially expressed genes (DEGs) by the functional enrichment analysis. According to our preliminary research, cell-specific TFs and TF-mediated GRNs are involved in the creation of SSCs. In order to maximize the induction efficiency of ESC differentiation into SSCs in vitro, hub SSC-specific genes and important SSC-specific TFs were identified, and sophisticated network regulation was proposed. According to our research, these genes and the hub proteins that they interact with may be able to shine a light on the pathophysiologies of infertility and aberrant germ cells. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a complex syndrome of neurological deficits due to stenosis or occlusion of the carotid and vertebral arteries for which there is still no effective treatment. Melatonin, a hormone secreted by the pineal gland, has multiple biological effects, such as antioxidant and anti-inflammatory properties, circadian rhythm regulation, and tissue regeneration, demonstrating potential applications in the treatment of IS. The aim of this study was to investigate key melatonin-regulated genes associated with IS using transcriptome sequencing and bioinformatics analyses and to explore their potential mechanisms of action in the disease process. We obtained gene expression data related to ischemic stroke (IS) from the Gene Expression Omnibus (GEO) database and identified candidate genes using machine learning algorithms. We then assessed the predictive power of these genes using PPI network analysis and diagnostic models. Finally, a series of enrichment analyses identified four key genes: ADM, PTGS2, MMP9, and VCAN. In addition, we determined the mRNA levels of these four key genes in an IS rat model using qPCR and found that all of these genes were significantly upregulated in the IS model compared to the control group, which is consistent with the results of previous analyses. Meanwhile, these genes have biological functions such as regulating vascular tone, participating in the inflammatory response, influencing tissue remodeling, and regulating cell adhesion and proliferation, playing key roles in the pathogenesis of IS. Therefore, we suggest that these four key genes may serve as prospective biomarkers for IS and help predict the risk of developing IS. In conclusion, this study elucidates for the first time the potential role of melatonin in the pathogenesis of IS and lays the foundation for in-depth studies on the functions of these key genes in the pathophysiology of IS and their potential applications in clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Molecular testing is recommended in patients with metastatic non-small cell lung cancer (NSCLC), but the extent of its use in Poland is unknown. The aim of the POL-MOL study was to investigate the frequency of using molecular testing in Polish patients with NSCLC. The invited Polish oncologists completed two questionnaires, and data for 1001 patients undergoing systemic treatment for NSCLC were collected. The use of molecular tests for the following genetic mutations was recorded: EGFR (del19, sub21), EGFR (other than del19/sub21), EGFR T790M, ALK (expression and rearrangement), RET, NTRK, ROS1, BRAF, HER2, and MET, as well as for immunochemical assessment of programmed cell death ligand 1 (PD-L1). Thanks to the weighting procedure, the results are representative of the population of Polish patients treated for NSCLC. Molecular tests were applied in 78% of patients with NSCL, 70% of patients with NSCLC not otherwise specified, and in 12% of patients with squamous cell carcinoma of the lung. The frequency of application increased with disease stage in all groups. In patients with squamous cell carcinoma, approximately 30% of tests for EGFR, ALK, and RET mutations were positive, which confirms the importance of testing at least a preselected subgroup of patients. [ABSTRACT FROM AUTHOR]