Signaling Genes Research Articles

Prostate Cancer: A Review of Genetics, Current Biomarkers and Personalised Treatments.

Prostate cancer is the second leading cause of cancer deaths in men, second only to lung cancer. Despite this, diagnosis and prognosis methods remain limited, with effective treatments being few and far between. Traditionally, prostate cancer is initially tested for through a prostate serum antigen (PSA) test and a digital rectum examination (DRE), followed by confirmation through an invasive prostate biopsy. The DRE and biopsy are uncomfortable for the patient, so less invasive, accurate diagnostic tools are needed. Current diagnostic tools, along with genes that hold possible biomarker uses in diagnosis, prognosis and indications for personalised treatment plans, were reviewed in this article. Several genes from multiple families have been identified as possible biomarkers for disease, including those from the MYC and ETS families, as well as several tumour suppressor genes, Androgen Receptor signalling genes and DNA repair genes. There have also been advances in diagnostic tools, including MRI-targeted and liquid biopsies. Several personalised treatments have been developed over the years, including those that target metabolism-driven prostate cancer or those that target inflammation-driven cancer. Several advances have been made in prostate cancer diagnosis and treatment, but the disease still grows year by year, leading to more and more deaths annually. This calls for even more research into this disease, allowing for better diagnosis and treatment methods and a better chance of patient survival.

Transcriptomic Plasticity of the Circadian Clock in Response to Photoperiod: A Study in Male Melatonin-Competent Mice.

Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel candidate genes for molecular mechanisms of photoperiod plasticity, we performed RNA sequencing on whole SCN dissected from mice raised in long (light:dark [LD] 16:8) and short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in mice subjected to long photoperiod, and in general, the timing of gene expression rhythms was advanced 4-6 h. However, a few genes showed significant delays, including Gem. There were significant changes in the expression of the clock-associated gene Timeless and in SCN genes related to light responses, neuropeptides, gamma aminobutyric acid (GABA), ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genes Prokr2 and Cck, as well as convergent regulation of the expression of 3 SCN light response genes, Dusp4, Rasd1, and Gem. Transcriptional modulation of Dusp4 and Rasd1 and phase regulation of Gem are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation of Prokr2 and Cck may critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity. Data are also available at http://circadianphotoperiodseq.com/, where users can view the expression and rhythmic properties of genes across these photoperiod conditions.

Molecular correlates of social adversity in breast cancer.

48 Background: Neighborhood disadvantage (ND) is associated with shorter breast cancer (BCa) survival independent of individual, tumor, and treatment factors, suggesting more aggressive tumor biology in women from disadvantaged neighborhoods. This study evaluates how differential DNA methylation (DNAm), gene expression, and biologic pathways are wired with each other to delineate the regulatory landscape of ND on BCa. Methods: We leveraged 55 geocoded ER+/HER2- BCa samples from Hispanic White women enrolled in a prospective genomic-epidemiologic cohort study. Objective ND was evaluated using the Area Deprivation Index (ADI) and subjective ND was evaluated using the patient-reported Neighborhood Social Environment Adversity Survey and the Everyday Expanded Discrimination Survey. We analyzed the association between ND and (1) DNAm, (2) RNA transcription and miRNAs, and (3) blood concentration levels of DNAm co-factors (B12 and folate) from the same patient. To evaluate how the DNAm/expressed pathways are wired with each other to delineate the regulatory landscape of ND in these tumors, we performed correlation analyses among CpGs, genes, and miRNAs in the same topologically associated domain (TAD). We used Spearman correlation as our metric and adjusted the resulting p-values to FDR values. Results: The cohort was divided into low ND (ADI<5; 31%) and a high ND (ADI>=5; 69%). There were no significant differences between groups by age, race/ethnicity, genetic ancestry, BMI, smoking/alcohol, subtype, stage, or OncotypeDX scores. We discovered that high ND exhibits epigenetic deregulation of immune pathways, consistent with our findings of lower circulating B12 in high ND, suggesting activation of immune pathways through reduced systemic availability of methyl donors. RNA-seq identified higher tumor infiltration of immune cells in patients from high ND (e.g., Interferon alpha and gamma responses and inflammatory responses) consistent with aggressive biology. Estrogen response genes were downregulated suggesting that patients from high ND may develop estrogen-resistant tumors. Higher subjective ND scores discovered epigenetic changes on cell adhesion and calcium signaling genes, along with gene expression of E2F targets and cell cycle’s G2M checkpoint, indicative of a more proliferative/stemness signature. TAD analysis discovered significant developmental, immune, and signaling pathways when correlating DNAm with gene expression (e.g., estrogen response and EMT). Conclusions: In this multi-omic matched cohort, we discovered differentially methylated/expressed pathways, consistent with aggressive biology, wired with each other to identify a novel regulatory landscape of ND on BCa. These findings can inform interventions such as improved access to healthy nutrition (B12) in ND/food deserts or targeted stress-reduction interventions based on our survey findings to ultimately reverse aggressive tumor biology and reduce BCa disparities by ND.

PLGA-Loaded Nedaplatin (PLGA-NDP) Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA) Induced Oral Carcinogenesis via Modulating Notch Signaling Pathway and Induces Apoptosis in Experimental Hamster Model.

The present study is designed to evaluate the nanotherapeutic efficacy of prepared PLGA-loaded Nedaplatin (PLGA-NDP) against 7,12-dimethyl benz(a)anthracene (DMBA)-induced experimental oral carcinogenesis in hamster buccal pouch (HBP) model. The buccal pouch of golden Syrian hamsters was painted with 0.5% DMBA in liquid paraffin three times a week for 14 weeks, ultimately leading to the development of oral squamous cell carcinoma (OSCC). Oral administration of PLGA-NDP (preinitiation) and Cisplatin delivery (5 mg/kg b.wt) started 1 week before the carcinogen exposure and continued on alternative days. Post-administration of PLGA-NDP (5 mg/kg b.wt) started 2 days after carcinogen (DMBA) induction until the end of the experiment. After the 14th week, we observed that DMBA-painted hamsters exhibited tumor formation, morphological alterations, and well-differentiated OSSC in addition to the responsive molecular proteins during oral carcinogenesis. Furthermore, immunoblotting analysis demonstrated that PLGA-NDP inhibits Notch signaling, as evidenced by downregulation of Bcl-Xl, Bcl-2, p21, PGE2, HGF, and CXCL12 proteins, and upregulation of p53 and Bax. This apoptotic response is crucial for PLGA-NDP to induce apoptosis. In addition, RT-PCR results showed that PLGA-NDP nanoparticles play a downregulatory role in the therapeutic action of the notch signaling gene (Notch1, Notch 2, Hes1, Hey1, and Jagged1) at the mRNA transcription level in HBP carcinoma. Taken together, these data indicate that PLGA-NDP is a potent inhibitor of oral carcinogenesis and the expansion of cells that specifically target the Notch signaling pathway indicates that obstructing Notch signaling could potentially serve as a new and innovative therapeutic approach for oral squamous cell carcinoma (OSCC).

Inflammaging and Brain Aging.

Progress made by the medical community in increasing lifespans comes with the costs of increasing the incidence and prevalence of age-related diseases, neurodegenerative ones included. Aging is associated with a series of morphological changes at the tissue and cellular levels in the brain, as well as impairments in signaling pathways and gene transcription, which lead to synaptic dysfunction and cognitive decline. Although we are not able to pinpoint the exact differences between healthy aging and neurodegeneration, research increasingly highlights the involvement of neuroinflammation and chronic systemic inflammation (inflammaging) in the development of age-associated impairments via a series of pathogenic cascades, triggered by dysfunctions of the circadian clock, gut dysbiosis, immunosenescence, or impaired cholinergic signaling. In addition, gender differences in the susceptibility and course of neurodegeneration that appear to be mediated by glial cells emphasize the need for future research in this area and an individualized therapeutic approach. Although rejuvenation research is still in its very early infancy, accumulated knowledge on the various signaling pathways involved in promoting cellular senescence opens the perspective of interfering with these pathways and preventing or delaying senescence.

Transcriptional regulation of hormone signalling genes in black pepper in response to Phytophthora capsici

IntroductionBlack pepper (Piper nigrum L.) is a non-model spice crop of significant agricultural and biological importance. The ‘quick wilt’ disease caused by the oomycete Phytophthora capsici is a major threat, leading to substantial crop loss. The molecular mechanisms governing the plant immune responses to this pathogen remain unclear. This study employs RNA sequencing and transcriptome analysis to explore the defense mechanisms of P. nigrum against P. capsici.ResultsTwo-month-old P. nigrum plantlets were subjected to infection with P. capsici, and leaf samples were collected at 6- and 12-hours post-inoculation. RNA was extracted, sequenced, and the resulting data were processed and assembled. Differential gene expression analysis was conducted to identify genes responding to the infection. Additionally, the study investigated the involvement of Salicylic acid (SA), Jasmonic acid (JA), and Ethylene (ET) signalling pathways. Our transcriptome assembly comprised 64,667 transcripts with 96.7% completeness, providing valuable insights into the P. nigrum transcriptome. Annotation of these transcripts identified functional categories and domains, provided details on molecular processes. Gene expression analysis identified 4,714 transcripts at 6 h post-infection (hpi) and 9,416 at 12 hpi as differentially expressed, revealing dynamic regulation of immune-related genes. Furthermore, the study investigated key genes involved in biosynthesis pathways of Salicylic acid, Jasmonic acid, and Ethylene signalling. Notably, we found differential regulation of critical genes associated with these pathways while comparing data before and after infection, thereby shedding light on their roles in defense mechanism in P. nigrum defense.ConclusionsThis comprehensive transcriptome analysis of P. nigrum response to P. capsici attack provides valuable insights into the plant defense mechanisms. The dynamic regulation of innate immunity and the involvement of key signalling pathways highlight the complexity of the plant-pathogen interaction. This study contributes to our understanding of plant immunity and offers potential strategies for enhancing P. nigrum resistance to this harmful pathogen.

Eco-Physiological and Genetic Basis of Drought Response Index in Rice—Integration Using a Temperate Japonica Mapping Population

The drought response index (DRI) is an indicator of drought tolerance after adjustment for variation in flowering date and potential yield under well-watered conditions. Using a temperate japonica mapping population of 97 recombinant inbred lines from a cross between Otomemochi (OTM) and Yumenohatamochi (YHM), we evaluated DRI during the reproductive stage under very severe drought in one year and under severe drought in the next year. DRI under very severe drought (−6.4 to 15.9) and severe drought (−3.9 to 8.3) positively correlated with grain dry weight under drought. Three QTLs for DRI were identified: RM3703–RM6911–RM6379 and RM6733–RM3850 both on chromosome 2 in both years combined; and RM8120–RM2615–RM7023 on chromosome 6 in the second year. The latter collocated with putative genes for signaling and defense mechanisms (e.g., PIN1B, BZIP46) revealed by database analysis. Top DRI lines retained root dry weight and had bigger steles. QTL-by-environment interaction had a greater relative contribution than the main effects of QTLs. Comparison with three previous studies revealed that the QTLs for DRI were unique to each experiment and/or population; most of them closely colocalized with reported drought-yield QTLs.

Bioinformatics analysis of ferroptosis in frozen shoulder

ObjectivesFrozen shoulder is a common shoulder disease that significantly affects the patient’s life and work. Ferroptosis is a new type of programmed cell death, which is involved in many diseases. However, there have been no studies reporting the relationship between frozen shoulders and ferroptosis. This study identified potential molecular markers of ferroptosis in frozen shoulders to provide more effective strategies for the treatment of frozen shoulders.MethodsGSE238053 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes to obtain differentially expressed genes (DEGs). The signaling pathways and biological functions of DEGs were performed by WebGestalt and Metascape. The interactions related to these DEGs and the key genes between frozen shoulders and ferroptosis was performed by STRING and Cytoscape. A frozen shoulders rat model was used to validate our predicted genes, Western Blot and qRT-PCR was used to assess the expression levels of our genes of interest.ResultsA total of 34 DEGs between GSE238053 and Ferroptosis Database were obtained, most of which were involved in the HIF-1 signaling pathway and inflammatory response. A protein–protein interaction network was obtained by Cytoscape and the key genes (IL-6, HMOX1 and TLR4) were screened by MCODE. Our results of Western Blot showed that the protein expression level of TLR4 and HMOX1 were elevated, and the protein level of IL-6 decreased in frozen shoulders rat model. The mRNA level after frozen shoulders showed that IL-6 was upregulated, whereas TLR4 and HMOX1were downregulated.ConclusionsThe results demonstrated that ferroptosis may affect the pathological process of frozen shoulders through these signaling pathways and genes. The identification of IL-6, HMOX1 and TLR4 genes can provide new therapeutic targets for frozen shoulders.

Histone variant H2AZ1 drives lung cancer progression through the RELA-HIF1A-EGFR signaling pathway

BackgroundA growing body of evidence indicates that histone variants play an oncogenic role in cancer progression. However, the role and mechanism of histone variant H2AZ1 in lung cancer remain poorly understood. In this study, we aim to identify novel functions and molecular mechanisms of H2AZ1 in lung cancer.MethodsWe analyzed H2AZ1 expression in lung adenocarcinoma using several RNA-seq and microarray datasets. Immunohistochemistry staining for H2AZ1 was performed on two sets of lung cancer tissue microarrays. To study the function of H2AZ1, we conducted assays for cell proliferation, colony formation, invasion, and migration. We employed CUT&Tag-seq, ATAC-seq, RNA-seq, and Western blotting to explore the regulatory patterns and potential mechanisms of H2AZ1 in lung adenocarcinoma.ResultsOur findings reveal that H2AZ1 is highly expressed in lung cancer and high levels of H2AZ1 mRNA are associated with poor patient survival. Silencing H2AZ1 impaired cell proliferation, colony formation, migration, and invasion. Mechanistically, our CUT&Tag-seq, ATAC-seq, and RNA-seq results showed that H2AZ1 is primarily deposited around TSS and affects multiple oncogenic signaling pathways. Importantly, we uncovered that H2AZ1 may drive lung cancer progression through the RELA-HIF1A-EGFR signaling pathway.ConclusionH2AZ1 plays an oncogenic role via several cancer-related pathways, including the RELA-HIF1A-EGFR axis in lung cancer. Intervention targeting H2AZ1 and its related signaling genes may have translational potential for precision therapy.

Identifying Key Genes as Progression Indicators of Prostate Cancer with Castration Resistance Based on Dynamic Network Biomarker Algorithm and Weighted Gene Correlation Network Analysis.

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the weighted gene co-expression network analysis (WGCNA) to identify key genes associated with the progression to a castration-resistant state in prostate cancer via the integration of single-cell and bulk RNA sequencing data. Based on the gene expression profiles of CRPC in the GEO dataset, the DNB method was used to clarify the condition of epithelial cells and find out the most significant transition signal DNB modules and genes included. Then, we calculated gene modules associated with the clinical phenotype stage based on the WGCNA. IHC was conducted to validate the expression of the key genes in CRPC and primary PCa patients Results:Nomograms, calibration plots, and ROC curves were applied to evaluate the good prognostic accuracy of the risk prediction model. Results: By combining single-cell RNA sequence data and bulk RNA sequence data, we identified a set of DNBs, whose roles involved in androgen-associated activities indicated the signals of a prostate cancer cell transition from an androgen-dependent state to a castration-resistant state. In addition, a risk prediction model including the risk score of four key genes (SCD, NARS2, ALDH1A1, and NFXL1) and other clinical-pathological characteristics was constructed and verified to be able to reasonably predict the prognosis of patients receiving ADT. Conclusions: In summary, four key genes from DNBs were identified as potential diagnostic markers for patients treated with ADT and a risk score-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions of CRPC.

Effect of AML-exosomes on the cellular and molecular properties of bone marrow mesenchymal stromal cells: Expression of JAK/STAT signaling genes

Purpose of studyDespite the various therapeutic options introduced for AML treatment, therapy resistance and relapse are still the main obstacles. It is well known that alterations in the bone marrow microenvironment (BMM) play a crucial role in leukemia growth and the treatment failure of AML. Evidence shows that exosomes alter the components of BMM in a way that support leukemia survival, leading to chemoresistance. In this study, we evaluated the effect of AML exosomes on the biological functions of human bone marrow mesenchymal stromal cells (h BM-MSCs), especially alteration in the expression of the JAK/STAT signaling genes, as a leukemia-favoring pathway. MethodExosomes were isolated from the HL-60 cell line and characterized using flow cytometry, Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS) technique. The exosome protein content was assessed using a bicinchoninic acid (BCA) protein assay kit in order to determine the concentration of exosomes. Subsequently, MSCs were treated with varying concentrations of AML exosomes, and data was obtained using MTT, cell cycle, apoptosis, and ki67 assays. Additionally, gene expression analysis was conducted through qRT-PCR. ResultAML exosomes regulated the viability and survival of MSCs in a concentration-dependent manner. The qRT-PCR data revealed that treatment with AML exosomes at a concentration of 50 μg/mL led to a significant upregulation of JAK2, STAT3, and STAT5 genes in MSCs. ConclusionBecause the JAK/STAT signaling pathway has been shown to play a role in the proliferation and survival of leukemic cells, our results suggest that AML exosomes stimulate MSCs to activate this pathway. This activation may impede AML cell apoptosis, potentially leading to chemoresistance and relapse.

Abstract C112: Hemp extract attenuates the proliferation of hepatocellular carcinoma cells- derive cells from racially diverse populations by inhibiting the Interferone-1 signaling pathway

Abstract Hepatocellular Carcinoma (HCC) is a highly fatal disease where race/ethnicity plays a vital role in determining incidence, mortality, and survival rates. The incidence of HCC is highest in Asia and Africa. Furthermore, there is a statistically significant increase in incidence and mortality and a decrease in 5-year survival rates in African American (AA)/Black patients compared to non-Hispanic white patients. The HCC patients might benefit from a holistic dietary approach, including hemp extract, along with their clinical treatment. Our bioinformatics analysis of The Cancer Genome Atlas (TCGA) identified the IFN-I signaling genes (ISGs) as the most significantly enriched pathway in AA/Black HCC patients. Consistent with this finding, RNA-seq analysis of archived HCC tumors from white (n=14) and AA/Black (n=18) patients further confirmed the upregulation of ISGs in these cohorts. Due to the severe toxicity of the currently available cancer treatments, there is also a demand for the development of alternative therapies with high efficacy and low side effects. We characterized 16 varieties of hemp for their polyphenols, antioxidation, CBDs, and terpenes contents and determined the effects of hemp extracts on the proliferation of HepG2 (white patients), Hep3B, and O/20 (Black patients), and HuH-7 (Asian Patient) HCC cell lines. Among different hemp varieties, KY-Plume extract showed the highest concentration of polyphenols, antioxidation activity, CBDA, and terpenes. It also most potently inhibited the growth of all HCC cell lines (IC50s 20-25 mg/ml), irrespective of their racial origin. Hemp treatment reduced the phosphorylation of the IFN downstream mediators, Jak-1, Tyk2, STAT1, and STAT2, in all HCC cell lines. In addition, hemp treatment also inhibited phosphorylation/activation of PI3K-Akt-mTOR and MAPK pathways. Currently, research is underway to identify the active chemical agent in hemp and test it on other patient-derived HCC lines and in an in vivo model. In conclusion, our data suggest that hemp can attenuate HCC proliferation by inhibiting multiple cellular signaling pathways, including the IFN-1 pathway. Our data suggest that HCC patients might benefit from a holistic dietary approach, including hemp extract, along with their clinical treatment. (Funded: Even-Allen-USDA and P20 CA264068-01-NIH). Citation Format: Rafat A Siddiqui, Haiwen Li, Ramesh Dhakal, Milton O Faison, Devanand Sarkar.. Hemp extract attenuates the proliferation of hepatocellular carcinoma cells- derive cells from racially diverse populations by inhibiting the Interferone-1 signaling pathway [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C112.

Clock protein LHY targets SNAT1 and negatively regulates the biosynthesis of melatonin in Hypericum perforatum.

Hypericum perforatum, also known as "natural fluoxetine," is a commonly used herbal remedy for treating depression. It is unclear whether melatonin in plants regulated by the endogenous circadian clock system is like in vertebrates. In this work, we found that the melatonin signal and melatonin biosynthesis gene, serotonin N-acetyltransferase HpSNAT1, oscillates in a 24-hour cycle in H. perforatum. First, we constructed a yeast complementary DNA library of H. perforatum and found a clock protein HpLHY that can directly bind to the HpSNAT1 promoter. Second, it was confirmed that HpLHY inhibits the expression of HpSNAT1 by targeting the Evening Element. Last, it indicated that HpLHY-overexpressing plants had reduced levels of melatonin in 12-hour light/12-hour dark cycle photoperiod, while loss-of-function mutants exhibited high levels, but this rhythm seems to disappear as well. The results revealed the regulatory role of LHY in melatonin biosynthesis, which may make an important contribution to the field of melatonin synthesis regulation.

Evolutionary Innovations in Conserved Regulatory Elements Associate With Developmental Genes in Mammals.

Transcriptional enhancers orchestrate cell type- and time point-specific gene expression programs. Genetic variation within enhancer sequences is an important contributor to phenotypic variation including evolutionary adaptations and human disease. Certain genes and pathways may be more prone to regulatory evolution than others, with different patterns across diverse organisms, but whether such patterns exist has not been investigated at a sufficient scale. To address this question, we identified signatures of accelerated sequence evolution in conserved enhancer elements throughout the mammalian phylogeny at an unprecedented scale. While different genes and pathways were enriched for regulatory evolution in different parts of the tree, we found a striking overall pattern of pleiotropic genes involved in gene regulatory and developmental processes being enriched for accelerated enhancer evolution. These genes were connected to more enhancers than other genes, which was the basis for having an increased amount of sequence acceleration over all their enhancers combined. We provide evidence that sequence acceleration is associated with turnover of regulatory function. Detailed study of one acceleration event in an enhancer of HES1 revealed that sequence evolution led to a new activity domain in the developing limb that emerged concurrently with the evolution of digit reduction in hoofed mammals. Our results provide evidence that enhancer evolution has been a frequent contributor to regulatory innovation at conserved developmental signaling genes in mammals.

Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children

Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Gene Expression Regulation and the Signal Transduction of Programmed Cell Death.

Cell death is of great significance in maintaining tissue homeostasis and bodily functions. With considerable research coming to the fore, it has been found that programmed cell death presents in multiple modalities in the body, which is not only limited to apoptosis, but also can be divided into autophagy, pyroptosis, ferroptosis, mitotic catastrophe, entosis, netosis, and other ways. Different forms of programmed cell death have disparate or analogous characteristics with each other, and their occurrence is accompanied by multiple signal transduction and the role of a myriad of regulatory factors. In recent years, scholars across the world have carried out considerable in-depth research on programmed cell death, and new forms of cell death are being discovered continually. Concomitantly, the mechanisms of intricate signaling pathways and regulators have been discovered. More critically, cancer cells tend to choose distinct ways to evade cell death, and different tumors adapt to different manners of death. Therefore, targeting the cell death network has been regarded as an effective tumor treatment strategy for a long time. The objective of our paper is to review the signaling pathways and gene regulation in several typical types of programmed cell death and their correlation with cancer.

Linking gut microbiota dysbiosis to molecular pathways in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and synaptic dysfunction. Emerging evidence suggests a significant relationship between gut microbiota and brain health, mediated through the gut-brain axis. Alterations in gut microbiota composition may influence AD progression by affecting molecular pathways and miRNA interactions. MethodsWe retrieved and analyzed microarray data from 34 tissue samples of AD patients and controls (GEO accession number GSE110298). Differentially expressed genes (DEGs) with the GCS score package in R, considering a p-value < 0.05 and logFC<-1 and logFC>1 to isolate significant gene clusters. Enrichment analysis of signaling pathways and gene ontology was conducted using Enrichr, KEGG, Panther, DAVID, and shiny GO databases. Protein-protein interactions were visualized with Networkanalyst and CytoScape. Gut microbiota in 200 CE patients was analyzed using next-generation sequencing (NGS) data from gutMDisorder and GMrepo databases. miRNA interactions were evaluated using miEAA, Targetscan, MienTurnet, and miRnet databases. ResultsSignificant reductions in microbial taxa, including Clostridia (LDA score −4.878208), Firmicutes (LDA score −4.817032), and Faecalibacterium (LDA score −4.40714), were observed in AD patients. Pathway analysis highlighted the involvement of Axon guidance, ErbB, and MAPK signaling pathways in AD. Venn diagram analysis identified 619 intersecting genes in brain and gut tissues, emphasizing pathways such as Axon Guidance and Cell Cycle. miRNA analysis revealed important regulatory miRNAs, including hsa-let-7c, hsa-mir-125b-2, and hsa-mir-145, which target key transcription factors involved in AD pathology. ConclusionThe study demonstrates significant dysbiosis in the gut microbiota of AD patients and underscores the potential role of gut microbiota in AD progression through altered signaling pathways and miRNA interactions. These findings highlight the need for further research into microbiota-based interventions as potential therapeutic strategies for AD.

Cognitive effects of early life exposure to PCBs: Sex-specific behavioral, hormonal and neuromolecular mechanisms involving the brain dopamine system.

Endocrine-disrupting chemicals (EDCs) are environmental toxicants that disrupt hormonal and neurodevelopmental processes. Among these chemicals, polychlorinated biphenyls (PCBs) are particularly concerning due to their resistance to biodegradation and tendency to bioaccumulate. PCBs affect neurodevelopmental function and disrupt the brain's dopamine (DA) system, which is crucial for attentional, affective, and reward processing. These disruptions may contribute to the rising prevalence of DA-mediated neuropsychiatric disorders such as ADHD, depression, and substance use disorders. Notably, these behaviors are sexually dimorphic, in part due to differences in sex hormones and their receptors, which are targets of estrogenic PCBs. Therefore, this study determined effects of early life PCB exposure on behaviors and neurochemistry related to potential disruption of dopaminergic signaling. Male and female Sprague Dawley rats were exposed to PCBs or vehicle perinatally and then underwent a series of behavioral tests, including the sucrose preference test to measure affect, conditioned orienting to assess incentive-motivational phenotype, and attentional set-shifting to evaluate cognitive flexibility and response latency. Following these tests, rats were euthanized, and we measured serum estradiol (E2), midbrain DA cells, and gene expression in the midbrain. Female rats exposed perinatally to A1221 exhibited decreased sucrose preference, and both male and female A1221 rats had reduced response latency in the attentional set-shifting task compared to vehicle counterparts. Conditioned orienting, serum estradiol (E2), and midbrain DA cell numbers were not affected in either sex; however, A1221-exposed male rats displayed higher expression of estrogen receptor alpha ( Esr1 ) in the midbrain and non-significant effects on other DA-signaling genes. Additionally, E2 uniquely predicted behavioral outcomes and DAergic cell numbers in A1221-exposed female rats, whereas DA signaling genes were predictive of behavioral outcomes in males. These data highlight sex-specific effects of A1221 on neuromolecular and behavioral phenotypes.

Genomic Insights into Disease Resistance in Sunflower (Helianthus annuus): Identifying Key Regions and Candidate Genes for Verticillium dahliae Resistance.

Sunflower (Helianthus annuus) is a globally significant field crop, and disease resistance is crucial for ensuring yield stability and crop quality. Verticillium dahliae is a notorious soilborne pathogen that causes Verticillium Wilt (VW) and threatens sunflower production worldwide. In this study, we conducted a comprehensive assessment of sunflower resistance to V. dahliae across 231 sunflower cultivar lines, from the Sunflower Association Mapping (SAM) population. We employed EMMAX and ridge regression best linear unbiased prediction (rrBLUP) and identified 148 quantitative trait loci (QTLs) and 23 putative genes associated with V. dahliae resistance, including receptor like kinases, cell wall modification, transcriptional regulation, plant stress signalling and defense regulation genes. Our enrichment and quantitative real-time PCR validation results highlight the importance of membrane vesicle trafficking in the sunflower immune system for efficient signaling and defense upon activation by V. dahliae. This study also reveals the polygenic architecture of V. dahliae resistance in sunflowers and provides insights for breeding sunflower cultivars resistant to VW. This research contributes to ongoing efforts to enhance crop resilience and reduce yield losses due to VW, ultimately benefiting sunflower growers and the agricultural sector.

169 Vitamin and mineral supplementation to gestating beef heifers: Fetal physiology and metabolic programming

Abstract Vitamins and minerals have key roles in hormone production and action, enzyme activity, tissue synthesis, oxygen transport, and energy production. These micronutrients are efficiently transferred from the dam to the fetus during gestation to be partitioned for metabolic use and stored as postnatal mineral reserves. Maternal nutrient intake is one of the main factors that influence the availability of vitamins and minerals to the fetus. Thus, an inadequate supply of these critical nutrients can have a long-lasting impact on offspring growth and health. Evidence suggests that biological processes regulating normal growth, development, and nutrient utilization are programmed in utero, even during the earliest developmental stages. Therefore, there is a critical need to evaluate the effects of micronutrient supplementation during gestation on fetal physiology and metabolic programming. Our research group has developed research models examining the impact of maternal vitamin and mineral supplementation (VTM, supplemented vs. NoVTM, not supplemented) during the periconceptual period or throughout gestation in beef heifers. A metabolomic analysis revealed that metabolites in the oxidative phosphorylation pathway were more abundant in the liver of fetuses from VTM than NoVTM dams, suggesting that a greater supply of micronutrients during the periconceptual period and first trimester of pregnancy may positively modulate mitochondrial energy metabolism in offspring. These changes in the abundance of metabolites suggested physiological adaptations to meet fetal metabolic needs. Further, high-resolution respirometry analysis revealed greater efficiency of energy utilization in small intestinal samples of neonatal calves from VTM dams. In fact, VTM offspring were heavier from weaning to breeding phase than NoVTM offspring, suggesting that maternal nutrition affects physiological mechanisms in utero that modulate offspring energetics and efficiency of nutrient utilization in the postnatal period. Furthermore, we reported increased concentrations of histidine, aspartate, and 12 out of 14 neutral amino acids in the allantoic fluid of VTM-supplemented dams. Finally, genes involved with amino acid transport in fetal liver were upregulated in response to VTM supplementation, highlighting the intricate relationship between maternal and fetal nutrition. Vitamin and mineral supplementation were also associated with changes in gene expression, biological processes and pathways in placental tissue at d 83 of gestation. We observed an upregulation of genes in the calcium signaling and cyclic guanosine monophosphate (CGMP)-PKG signaling pathways in response to micronutrient supplementation. Calcium-mediated systems may modulate cell proliferation and steroidogenic activity in bovine placentomes, while CGMP-PKG plays a key role in vascular homeostasis. Placental blood vessel vascularity at term was indeed increased in heifers supplemented throughout gestation, emphasizing the importance of micronutrient supplementation beyond early pregnancy. Altogether, our findings suggest that vitamin and mineral supplementation in the periconceptual period and during gestation play a pivotal role in fetal metabolic programming with consequences extending to the postnatal period.