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Background: Exhaustion is a key factor that influences the efficacy of chimeric antigen receptor T (CAR-T) cells. Our previous study demonstrated that a bromodomain protein 4 (BRD4) inhibitor can revise the phenotype and function of exhausted T cells from leukemia patients. This study aims to elucidate the mechanism by which a BRD4 inhibitor reduces CAR-T cell exhaustion using single-cell RNA sequencing (scRNA-Seq). Methods: Exhausted CD123-specific CAR-T cells were prepared by co-culture with CD123 antigen-positive MV411 cells. After elimination of MV411 cells and upregulation of inhibitory receptors on the surface, exhausted CAR-T cells were treated with a BRD4 inhibitor (JQ1) for 72 h. The CAR-T cells were subsequently isolated, and scRNA-Seq was conducted to characterize phenotypic and functional changes in JQ1-treated cells. Results: Both the proportion of exhausted CD8+ CAR-T cells and the exhausted score of CAR-T cells decreased in JQ1-treated compared with control-treated cells. Moreover, JQ1 treatment led to a higher proportion of naïve, memory, and progenitor exhausted CD8+ CAR-T cells as opposed to terminal exhausted CD8+ CAR-T cells accompanied by enhanced proliferation, differentiation, and activation capacities. Additionally, with JQ1 treatment, BATF activity and expression in naïve, memory, and progenitor exhausted CD8+ CAR-T cells decreased, whereas EGR1 activity and expression increased. Interestingly, AML patients with higher EGR1 and EGR1 target gene ssGSEA scores, coupled with lower BATF and BATF target gene ssGSEA scores, had the best prognosis. Conclusions: Our study reveals that a BRD4 inhibitor can reduce CAR-T cell exhaustion and block exhausted T cell terminal differentiation by downregulating BATF activity and expression together with upregulating EGR1 activity and expression, presenting an approach for improving the effectiveness of CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal. [ABSTRACT FROM AUTHOR]

Bovine mastitis is a complex infectious disease that develops in the mammary gland, predominantly caused by a bacterial infection of mammary tissue. Genetic variability of mastitis is well established and depends upon different quantitative trait loci (QTL) related to mastitis resistance or susceptibility. The susceptibility is often attributed to single-nucleotide polymorphisms (SNPs) in the variable cow breed genomes. Several global investigative attempts have resulted in studies mapping mastitis to the variations in the relevant genes. Reports have been attributed to dramatic genetic expression changes in Toll-Like Receptor 4 (TLR4) genes in mastitis-positive cows. However, the mechanism behind this variable genetic expression of TLR4 genes has been studied poorly. The present study aims to investigate SCM through various screening tests like somatic cell count (SCC), electric conductivity (EC), pH, and California mastitis test (CMT) in milk samples. This study also aims to investigate possible mechanisms behind this variable expression of TLR4 by comparative SNP evaluation and transcriptional factor profile mining. So that the important genetic mutations and effects thereof can be exploited in selecting specific breeds with higher mastitis resistance and milk yield. Seventy Holstein Frisian (HF) crossbred dairy cows were selected in the present study. The animals were screened based on various diagnostic tests (SCC, pH, EC, and CMT). Blood samples (5 mL) were collected for extraction of DNA followed by amplification of PPR1 and PPR2 of the promoter region and 5′UTR of the bovine TLR4 gene using specific primers. Sanger's enzymatic DNA sequencing technique sequenced the amplified PCR products. Further, the identification of SNPs was done through various bioinformatic tools used in this study. The findings of the present study revealed that CMT, EC, pH, and SCC could be used for the early detection of subclinical mastitis. In the present study, a significant increase in the EC, pH, and SCC in milk samples of animals affected with SCM was found in comparison to the healthy animals. The present study also revealed 16 SNPs falling in TLR4 promoter and 5′ untranslated region (5′UTR) sequences in mastitis-positive genotypes compared to reference genomes. The study also investigates the potential transcriptional factor program deployed in response to variable mastitis development resistance. In the present study, the allelic and genotype frequencies of all SNP variants in the three regions viz., PPR1, PPR2, and 5′UTR, were the same indicating the absence of heterozygous condition at the respective loci. The present study has wide applicability for researchers developing mastitis-resistant breeding programs and the data generated may aid in the selection of better genetic breeds. The transcription factor binding profiles can serve as concrete leads about the studies on bovine mastitis at the molecular level and may also aid global research groups working on transcription factor (TF)-based molecular pathology of mastitis. [ABSTRACT FROM AUTHOR]

Abstract Background Exhaustion is a key factor that influences the efficacy of chimeric antigen receptor T (CAR-T) cells. Our previous study demonstrated that a bromodomain protein 4 (BRD4) inhibitor can revise the phenotype and function of exhausted T cells from leukemia patients. This study aims to elucidate the mechanism by which a BRD4 inhibitor reduces CAR-T cell exhaustion using single-cell RNA sequencing (scRNA-Seq). Methods Exhausted CD123-specific CAR-T cells were prepared by co-culture with CD123 antigen-positive MV411 cells. After elimination of MV411 cells and upregulation of inhibitory receptors on the surface, exhausted CAR-T cells were treated with a BRD4 inhibitor (JQ1) for 72 h. The CAR-T cells were subsequently isolated, and scRNA-Seq was conducted to characterize phenotypic and functional changes in JQ1-treated cells. Results Both the proportion of exhausted CD8+ CAR-T cells and the exhausted score of CAR-T cells decreased in JQ1-treated compared with control-treated cells. Moreover, JQ1 treatment led to a higher proportion of naïve, memory, and progenitor exhausted CD8+ CAR-T cells as opposed to terminal exhausted CD8+ CAR-T cells accompanied by enhanced proliferation, differentiation, and activation capacities. Additionally, with JQ1 treatment, BATF activity and expression in naïve, memory, and progenitor exhausted CD8+ CAR-T cells decreased, whereas EGR1 activity and expression increased. Interestingly, AML patients with higher EGR1 and EGR1 target gene ssGSEA scores, coupled with lower BATF and BATF target gene ssGSEA scores, had the best prognosis. Conclusions Our study reveals that a BRD4 inhibitor can reduce CAR-T cell exhaustion and block exhausted T cell terminal differentiation by downregulating BATF activity and expression together with upregulating EGR1 activity and expression, presenting an approach for improving the effectiveness of CAR-T cell therapy.

Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma, associated with poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is limited. Bromodomain and extra-terminal (BET) proteins are involved in both physiological and pathological events. However, the role of BET proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. In addition, the targeted inhibition of BET proteins altered several other epigenetic regulators, including DNA methylases, histone modification, and m6A regulators. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment. [ABSTRACT FROM AUTHOR]

Transcriptional factors-based biosensors are commonly used in metabolic engineering for inducible control of gene expression and related applications such as high-throughput screening and dynamic pathway regulations. Mining for novel transcriptional factors is essential for expanding the usability of these toolsets. Here, we report the identification, characterization, and engineering of a phenolic acid responsive regulator PadR from Bacillus amyloliquefaciens (BaPadR). This BaPadR-based biosensor system showed a unique ligand preference and exhibited a high output strength comparable to that of commonly used inducible expression systems. Through engineering the DNA binding region of BaPadR, we further enhanced the dynamic range of the biosensor system. The DNA sequences that are responsible for BaPadR recognition were located by promoter truncation and hybrid promoter building. To further explore the tunability of the sensor system, base substitutions were performed on the BaPadR binding region of the phenolic acid decarboxylase promoter (PpadC) and the hybrid promoter. This novel biosensor system can serve as a valuable tool in future synthetic biology applications.

Rhizophoraceae has two terrestrial genera and four marine genera. Marine and terrestrial genera have evolved distinct adaptive characteristics to adapt to their environment, among which viviparous reproduction is the most unique. To investigate the genetic foundations difference underlying the adaptive mechanisms of marine–terrestrial genera, we compared the transcriptome of eight tissues (root, stem, leaf, flower, ovule, fruit, seed and embryo) of Kandelia obovata and Carallia brachiata, and found that the mature reproductive organs (fruit, seed and embryo) of K. obovata did not reduce metabolic activity compared to C. brachiata. The reproductive organs of K. obovata were regulated by the same gene set as vegetative organs. This contrasted with C. brachiata. Eight kinds of hormone transduction genes were up-regulated in the seed of K. obovata. Finally, and most importantly, the transcriptional factors AP2 and ARF families were significantly higher expressed in the reproductive organs of K. obovata than those of C. brachiata. At the same time, the ERF family was more expressed in its roots. The findings suggested that hormone transduction may contribute to viviparous initiation. Transcriptional factors were quite crucial for mangrove adaptation to wetlands.

Soybean plant architecture has a significant impact on yield potential, but the genetic underpinnings of key architectural traits remain elusive. The primary objective of this study was to explore the genetic foundations underlying main stem node number (MSN) in soybeans. Recombinant inbred lines (RILs) contained a 234 individual derived from crosses between two cultivars Zhonghuang35 (ZH35) and Jindou21 (JD21) was evaluated for seed hardness across 3 years (2013, 2014, and 2015 in Gansu). Markedly, the parent varieties, shown significant differences in MSN. Also, the RIL population exhibited a wide range of genetic variation in MSN. A high-density genetic map composed of 8,078 specific-locus amplified fragment (SLAF) markers, spanning 3,480.98 centimorgans (cM) with an average inter-marker distance of 0.59 cM were used to construct linkage map. Using ICIM analysis identified a total of 23 Quantitative Trait Loci (QTLs) across the 20 chromosome, of which five QTLs were detected in multiple years in Chr.6. Notably, we identified a stable major QTL, qMSN-6-4, explaining up to 24.81% of phenotypic variation. This QTL govern seven candidate genes with potential roles in regulating MSN development in soybean, including Glyma.06G027500 with a domain of unknown function, Glyma.06G027600 involved in proton transport, Glyma.06G027700 linked to proteolysis, Glyma.06G027900 related to transcriptional regulation, and Glyma.06G028000 and Glyma.06G028050 associated with membrane functions. The RT-PCR analysis confirmed that these genes were expressed differently between the parental lines this supports the idea that they may play a role in determining MSN. Glyma.06G027500 and Glyma.06G027600 showing higher expression in JD21 leaves and nodes, while Glyma.06G027700 and Glyma.06G028000 exhibited increased expression in ZH35 stems, highlighting their distinct roles in transcription regulation, membrane activities, and protein degradation that contribute to MSN formation in soybean. This study offers valuable insights into the genetic mechanisms governing soybean MSN, providing a foundation for future research and crop improvement efforts.

Camelina (Camelina Sativa) is a hexaploid dicotyledonous plant from the Brassicaceae family, which is very similar to the Arabidopsis. The number of camelina chromosomes is 40=2n. WRKY transcription factors are one of the most important gene families in plants that play an important role in regulating growth and development and response to various stresses. In this research, 224 WRKY genes were identified in the camelina plant by searching the database, and the chromosomal position, gene length, and conserved motifs were identified in the camelina plant based on the Arabidopsis. Also, in this study, in order to validate the research, 2 genes WRKY8 and WRKY57 under drought stress were investigated by the qPCR method. The results indicated that both the above-mentioned genes were strongly expressed under drought stress conditions in tolerant varieties compared to normal conditions, but the trend was opposite in sensitive varieties. This study has provided acceptable and valuable information for studying the evolution and function of the WRKY gene family in camelina.

Camelina (Camelina Sativa) is a hexaploid dicotyledonous plant from the Brassicaceae family, which is very similar to the Arabidopsis. The number of camelina chromosomes is 40=2n. WRKY transcription factors are one of the most important gene families in plants that play an important role in regulating growth and development and response to various stresses. In this research, 224 WRKY genes were identified in the camelina plant by searching the database, and the chromosomal position, gene length, and conserved motifs were identified in the camelina plant based on the Arabidopsis. Also, in this study, in order to validate the research, 2 genes WRKY8 and WRKY57 under drought stress were investigated by the qPCR method. The results indicated that both the above-mentioned genes were strongly expressed under drought stress conditions in tolerant varieties compared to normal conditions, but the trend was opposite in sensitive varieties. This study has provided acceptable and valuable information for studying the evolution and function of the WRKY gene family in camelina. [ABSTRACT FROM AUTHOR]

In the filamentous ascomycete Aspergillus nidulans, at least three high hierarchy transcription factors are required for growth at extracellular alkaline pH: SltA, PacC and CrzA. Transcriptomic profiles depending on alkaline pH and SltA function showed that pacC expression might be under SltA regulation. Additional transcriptional studies of PacC and the only pH-regulated pal gene, palF, confirmed both the strong dependence on ambient pH and the function of SltA. The regulation of pacC expression is dependent on the activity of the zinc binuclear (C6) cluster transcription factor PacX. However, we found that the ablation of sltA in the pacX− mutant background specifically prevents the increase in pacC expression levels without affecting PacC protein levels, showing a novel specific function of the PacX factor. The loss of sltA function causes the anomalous proteolytic processing of PacC and a reduction in the post-translational modifications of PalF. At alkaline pH, in a null sltA background, PacC72kDa accumulates, detection of the intermediate PacC53kDa form is extremely low and the final processed form of 27 kDa shows altered electrophoretic mobility. Constitutive ubiquitination of PalF or the presence of alkalinity-mimicking mutations in pacC, such as pacCc14 and pacCc700, resembling PacC53kDa and PacC27kDa, respectively, allowed the normal processing of PacC but did not rescue the alkaline pH-sensitive phenotype caused by the null sltA allele. Overall, data show that Slt and PacC/Pal pathways are interconnected, but the transcription factor SltA is on a higher hierarchical level than PacC on regulating the tolerance to the ambient alkalinity in A. nidulans. [ABSTRACT FROM AUTHOR]

Background: Rhizobium giardinii has been demonstrated to colonize the roots of a variety of legume species, including common beans, and to increase nitrogen fixation. This suggests that Rhizobium giardinii might be a beneficial tool for sustainable agriculture by lowering dependency on synthetic nitrogen fertilizers and enhancing soil fertility. Understanding the regulatory components in the R. giardinii A3AY_RS01 genes might also lead to the creation of innovative ways for increasing the effectiveness of nitrogen fixation in other agriculturally important bacteria. Therefore, this study was aimed to predict regulatory element of R. giardinii DNA-binding response regulator A3AY_RS01 genes. Results: The locations for 19 % of the Transcriptional start site (TSSs) were within −300 bp relative to the start codon and ten candidate motifs were identified that are shared by at least 50 % of the R. giardinii A3AY_RS01 promoter input sequences from both strands. Motif 1 was revealed as the common promoter motif for all of R. giardinii A3AY_RS01 genes that serves as binding sites for TFs involved in the expression regulation of these genes. Hence, it was revealed that Motif 1 may serve as the binding site chiefly for Ferric uptake regulator (Fur) transcription factor family to regulate expression of A3AY_RS01 genes. High CpG density in the promoter than body regions were observed for most of the genes except for A3AY_RS0102950, A3AY_RS0120195 and A3AY_RS0131150 genes. Nonetheless, promoter areas were richer than body regions in both techniques. Conclusions: MV1 motif can serve as a binding site for the Fur transcription factor gene family in R. giardinii to regulate the expression of R. giardinii A3AY_RS01 genes. R. giardinii A3AY_RS01 genes are rich in CpG Islands, and play an important role in the regulation of the gene expression of nitrogen fixing in this bacterium.

One of the most significant environmental challenges to crop growth and yield worldwide is soil salinization. Salinity lowers soil solution water potential, causes ionic disequilibrium and specific ion effects, and increases reactive oxygen species (ROS) buildup, causing several physiological and biochemical issues in plants. Plants have developed biological and molecular methods to combat salt stress. Salt-signaling mechanisms regulated by phytohormones may provide additional defense in salty conditions. That discovery helped identify the molecular pathways that underlie zinc-oxide nanoparticle (ZnO-NP)-based salt tolerance in certain plants. It emphasized the need to study processes like transcriptional regulation that govern plants' many physiological responses to such harsh conditions. ZnO-NPs have shown the capability to reduce salinity stress by working with transcription factors (TFs) like AP2/EREBP, WRKYs, NACs, and bZIPs that are released or triggered to stimulate plant cell osmotic pressure-regulating hormones and chemicals. In addition, ZnO-NPs have been shown to reduce the expression of stress markers such as malondialdehyde (MDA) and hydrogen peroxide (H2O2) while also affecting transcriptional factors. Those systems helped maintain protein integrity, selective permeability, photosynthesis, and other physiological processes in salt-stressed plants. This review examined how salt stress affects crop yield and suggested that ZnO-NPs could reduce plant salinity stress instead of osmolytes and plant hormones. [ABSTRACT FROM AUTHOR]

The storage of peach fruits at 4–5 °C can easily lead to chilling injury and greatly reduce the quality and commercial value of peach fruits. In this study, two kinds of peach fruits (CX and CM) were selected to analyze the mechanisms of chilling injury in fruits with different chilling sensitivity by means of their lipidomic, transcriptome, and dynamic changes in plant hormones. We found that the ethylene, abscisic acid (ABA), and lipid contents changed differently between CX and CM. The ABA and dilactosyl diacylglycerol (DGDG) contents significantly increased after refrigeration in CM fruit, leading to strong cold resistance. However, low temperatures induced a greater accumulation of ethylene, phospholipids, and ABA-GE in CX fruit than in CM fruit, eventually leading to more severe CI symptoms in CX fruit. Additionally, a transcriptional regulatory network for CM and CX fruits during cold storage was constructed, providing a new theoretical reference for the cultivation of cold-resistant peach cultivars and the development of postharvest preservation technology. [ABSTRACT FROM AUTHOR]

As a dominating air pollutant, atmospheric fine particulate matter within 2.5 μm in diameter (PM2.5) has attracted increasing attention from the researchers all over the world, which will lead to various adverse effects on the central nervous system (CNS), yet the potential mechanism is unclear. In this study, the microglia (BV2 cell line) were exposed to different concentrations of PM2.5 (5, 10 and 20 μg/cm2) for 24 h. It was found that PM2.5 could result in adverse effects on microglia such as decreased cell viability, structural damage and even cell death. And it was reported that long non-coding RNAs (lncRNAs) could participate in multitudinous neurological diseases. Therefore, the microarray analysis was conducted in order to disclose the underlying neurotoxicity mechanism of PM2.5 by ascertaining the differentially expressed lncRNAs (DElncRNAs). The consequences indicated that the DElncRNAs were enriched in various biological pathways, including ferroptosis, IL-17 signaling pathway and NOD-like receptor signaling pathway. Moreover, the cis- and trans-regulated mRNAs by DElncRNAs as well as the corresponding transcriptional factors (TFs) were observed, such as CEBPA, MYC, MEIS1 and KLF4. In summary, our study supplies some candidate libraries and potential preventive target against PM2.5-induced toxicity through targeting lncRNAs. Furthermore, the post-transcriptional regulation will contribute to the future research on PM2.5-induced neurotoxicity.

Background: Human embryonic stem cell (hESC)-derived endothelial cells (ECs) possess therapeutic potential in many diseases. Cytokine supplementation induction and transcription factor overexpression have become two mainstream methods of hESC-EC induction. Single-cell RNA-seq technology has been widely used to analyse dynamic processes during hESC-EC induction and components of induced endothelial cells. However, studies that used single-cell RNA-seq are mainly based on cytokine supplementation methods. In this study, we used a high-efficiency human embryonic stem cell-endothelial cell line (hESC-EC) called the "FLI1-PKC system" as a research model and employed single-cell RNA sequencing (scRNA-seq) to investigate the transcriptional landscape and cellular dynamics. Methods: The high-efficiency hESC-EC induction (FLI1-PKC) system was established in our previous study. We applied single-cell RNA sequencing (scRNA-seq) of the differentiated cells at different time points and investigated the gene expression profiles. Results: The FLI1-PKC induction system can directionally differentiate hESCs into mature endothelial cells with all the requisite functions. Unlike other hES-EC induction protocols, the FLI1-PKC method follows a different induction route; nonetheless, the transcriptome of induced endothelial cells (iECs) remains the same. The elevated number of activated transcription factors may explain why the FLI1-PKC system is more effective than other hES-EC protocols. Conclusion: Our study has presented a single-cell transcriptional overview of a high-efficiency hESC-EC induction system, which can be used as a model and reference for further improvement in other hESC induction systems. [ABSTRACT FROM AUTHOR]

Lycopene cyclases (LCYs) are a key branching point in regulating the carotenoid biosynthesis pathway in plants. Bixa orellana L. is characterized by the presence in its seed of bixin, an apocarotenoid of significant importance in the food, pharmaceutical, and cosmetic industries. Gene analysis provides the opportunity to investigate the LCY gene structure in plant species and its relationship with the synthesis of carotenoids. Coding sequences of the LCY genes were retrieved from a B. orellana genome DNA. Boβ-LCY1 and Boβ-LCY2 genes exhibit 100% of identity to their respective cDNA accessions, and exhibit a single coding region of 1512 bp (504 aa) and 1495 bp (498 aa), respectively. In contrast, Boε-LCY gene shows a coding region of 1581 bp (527 aa) with 10 introns of diverse lengths. Putative Transcription Factors (TFs) binding sites were upstream (3000 bp) identified for each LCY gene. TFs cover two groups, one with the categories of photosynthesis, reproduction, and oxidative processes that are frequent. The second one with the categories of defense, cell cycle, signaling, and carbohydrate metabolism, which are poorly represented. Besides, repetitive DNA elements showed motifs and proteins related to LTR from the Ty3/Gypsy family, were associated with the TFs regions. In general, TFs vary in the different BoLCY genes, being more abundant in the Boε-LCY gene. LCY expression analyzed from a transcriptome database, and validated by RT-qPCR, shows an upregulation of the three LCYs, mainly oriented to the synthesis of essential carotenoids in photosynthetic tissues (leaves), as well as an upregulation of the Boβ-LCY2 gene in the non-photosynthetic tissues (firsts seed development stages) related to the bixin accumulation. [ABSTRACT FROM AUTHOR]

In the filamentous ascomycete Aspergillus nidulans, at least three high hierarchy transcription factors are required for growth at extracellular alkaline pH: SltA, PacC and CrzA. Transcriptomic profiles depending on alkaline pH and SltA function showed that pacC expression might be under SltA regulation. Additional transcriptional studies of PacC and the only pH-regulated pal gene, palF, confirmed both the strong dependence on ambient pH and the function of SltA. The regulation of pacC expression is dependent on the activity of the zinc binuclear (C6) cluster transcription factor PacX. However, we found that the ablation of sltA in the pacX− mutant background specifically prevents the increase in pacC expression levels without affecting PacC protein levels, showing a novel specific function of the PacX factor. The loss of sltA function causes the anomalous proteolytic processing of PacC and a reduction in the post-translational modifications of PalF. At alkaline pH, in a null sltA background, PacC72kDa accumulates, detection of the intermediate PacC53kDa form is extremely low and the final processed form of 27 kDa shows altered electrophoretic mobility. Constitutive ubiquitination of PalF or the presence of alkalinity-mimicking mutations in pacC, such as pacCc14 and pacCc700, resembling PacC53kDa and PacC27kDa, respectively, allowed the normal processing of PacC but did not rescue the alkaline pH-sensitive phenotype caused by the null sltA allele. Overall, data show that Slt and PacC/Pal pathways are interconnected, but the transcription factor SltA is on a higher hierarchical level than PacC on regulating the tolerance to the ambient alkalinity in A. nidulans.

Epigenetics generally involves genetic control by factors other than our own DNA sequence. Recent research has focused on delineating the mechanisms of two major epigenetic phenomena: DNA methylation and histone modification. As epigenetics involves many cellular processes, it is no surprise that it can also influence disease-associated gene expression. A direct link between respiratory infections, host cell epigenetic regulations, and chronic lung diseases is still unknown. Recent studies have revealed bacterium- or virus-induced epigenetic changes in the host cells. In this review, we focused on respiratory pathogens (viruses, bacteria, and fungi) induced epigenetic modulations (DNA methylation and histone modification) that may contribute to lung disease pathophysiology by promoting host defense or allowing pathogen persistence. [ABSTRACT FROM AUTHOR]

Pseudomonas savastanoi pv. glycinea (Psg) causes bacterial blight on soybeans. Among Psg mutants that we previously generated by transposon mutagenesis to identify potential virulence factors, mutant VTP20 had reduced virulence. Genetic analysis of VTP20 revealed a mutation in operon PsgB076_26935-PsgB076_26940 (vt35-vt40). The vt35-vt40 operon is a toxin–antitoxin (TA) system, in which vt35 is functionally considered an antitoxin component. However, the function of this antitoxin in the vt35-vt40 TA system in Psg is unclear. Thus, here we used an overexpression approach to analyze the effects of vt35 on Psg virulence and found that Psg-vt35-OE caused less severe disease than Psg WT did in spray-inoculated and in syringe-infiltrated soybean leaves. Vt35 also regulated gene expression for multiple extracytoplasmic function (ECF) sigma factors during infection. These results suggest that Vt35 plays a central regulatory role in Psg virulence by regulating virulence factors and controlling alternate sigma factors. [ABSTRACT FROM AUTHOR]

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BackgroundNormal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.ResultsSC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two-sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12.ConclusionsIn normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

Diabetes mellitus is a significant health problem for medicine and economics. In 80–90% of cases, it is type 2 diabetes (T2DM). An essential aspect for people with T2DM is to control blood glucose levels and avoid significant deviations. Modifiable and non-modifiable factors influence the incidence of hyperglycemia and, sometimes, hypoglycemia. The lifestyle modifiable factors are body mass, smoking, physical activity, and diet. These affect the level of glycemia and impact molecular changes. Molecular changes affect the cell’s primary function, and understanding them will improve our understanding of T2DM. These changes may become a therapeutic target for future therapy of type 2 diabetes, contributing to increasing the effectiveness of treatment. In addition, the influence of external factors (e.g., activity, diet) on each domain of molecular characterization has gained importance towards a better understanding of their role in prevention. In the current review, we aimed to collect scientific reports on the latest research about modifiable factors connected with the style of life which affect the glycemic level in the context of molecular discoveries.

Abstract Background Mesenchymal stem cells (MSCs) possess the potential to differentiate into chondrocytes, which makes them an ideal source for healing cartilage defects. Here, we seek to identify the essential genes participating in MSCs chondrogenesis. Methods Human MSCs were induced for chondrogenesis for 7, 14, and 21 days using a high-density micromass culture system, and RNA was extracted for RNA-seq. Results A total of 6247 differentially expressed genes (DEGs) were identified on day 7, and 85 DEGs were identified on day 14. However, no significant DEGs was identified on day 21. The top 30 DEGs at day 7, including COL9A3, COL10A1, and CILP2, are closely related to extracellular matrix organization. While the top 30 DEGs at day 14 revealed that inflammation-related genes were enriched, including CXCL8, TLR2, and CCL20. We also conducted protein–protein interaction (PPI) networks analysis using the search tool for the retrieval of interacting genes (STRING) database and identified key hub genes, including CXCL8, TLR2, CCL20, and MMP3. The transcriptional factors were also analyzed, identifying the top 5 TFs: LEF1, FOXO1, RORA, BHLHE41, and SOX5. We demonstrated one particular TF, RORA, in promoting early MSCs chondrogenesis. Conclusions Taken together, our results suggested that these DEGs may have a complex effect on MSCs chondrogenesis both synergistically and solitarily.

The Signal Transducer and Activator of Transcription 3 (STAT3) pharmacological targeting is regarded as a prospective approach to treat cancer, autoimmune disorders, or inflammatory diseases. We have developed a series of reporters of the STAT3, NF-κB, Nrf2, metal-responsive transcription factor-1 (MTF-1), and hypoxia-inducible factor 1α (HIF-1α) transcriptional activation in human monocyte-macrophage line THP-1. The reporter lines were employed to test a set of hydrazide-hydrazones as potential STAT3 inhibitors. A hydrazide-hydrazone library composed of 70 binary combinations of 7 carbonyl and 10 hydrazide components, including a STAT3 inhibitor clinical drug nifuroxazide, has been assembled and screened by the reporters. For the library as a whole, significant correlations between responses of the STAT3 and NF-κB or the STAT3 and HIF-1α reporters in THP-1 monocytes were found. For selected inhibitory combinations, respective hydrazide-hydrazones have been prepared and tested individually. The most potent 2-acetylpyridine 4-chlorobenzoylhydrazone exhibited the STAT3 inhibitory potential significantly exceeding that of nifuroxazide (ED50 2 vs 50 μM respectively) in THP-1 cells. We conclude that insulated reporter transposons could be a useful tool for drug discovery applications. [ABSTRACT FROM AUTHOR]

The storage of peach fruits at 4–5 °C can easily lead to chilling injury and greatly reduce the quality and commercial value of peach fruits. In this study, two kinds of peach fruits (CX and CM) were selected to analyze the mechanisms of chilling injury in fruits with different chilling sensitivity by means of their lipidomic, transcriptome, and dynamic changes in plant hormones. We found that the ethylene, abscisic acid (ABA), and lipid contents changed differently between CX and CM. The ABA and dilactosyl diacylglycerol (DGDG) contents significantly increased after refrigeration in CM fruit, leading to strong cold resistance. However, low temperatures induced a greater accumulation of ethylene, phospholipids, and ABA-GE in CX fruit than in CM fruit, eventually leading to more severe CI symptoms in CX fruit. Additionally, a transcriptional regulatory network for CM and CX fruits during cold storage was constructed, providing a new theoretical reference for the cultivation of cold-resistant peach cultivars and the development of postharvest preservation technology.

Secondary metabolites in plants have been recognized as a novel basis of potential bio-pesticides, paving the way for their use in sustainable agriculture. Plant secondary metabolites have pivotal roles in plant-pathogen interactions. Some important secondary metabolites of plants are terpenoids, flavanols, flavones, etc., are stress-inducible phytochemicals playing an important role in plant immune response development. Pathogen enters into host cell, multiply and utilise the biological mechanism of plants, causing a hazard to world food assembly. Under stressed circumstances, plants evolve a powerful and intricate system of growth and defensive action. On the other hand, transcription factors (TFs) assist host plants to counter adverse environments by acting as mediators of stress signal and regulating the stress-responsive gene expression. The transcriptional and post-transcriptional manipulation of transcriptional factors is capable of aid in molecular breeding and genetic modification meant for improved secondary metabolite synthesis. Although the presence of numerous secondary metabolites has been established in plant life, very slight is known about their interaction with pathogens and the specific mechanisms involved in leading to plant immunity. Chemical pesticides are wreaking havoc on our environment. As a consequence, environmental-friendly alternatives to disease management, like plant-based metabolites, should be explored. In this appraisal, we have reviewed plant secondary metabolites in relation to pathogens, their contribution to innate immunity, mechanism of action, and regulation of TFs in response to combating plant infections in an eco-friendly approach.

One of the adverse outcomes of acute inflammatory response is progressing to the chronic stage or transforming into an aggressive process, which can develop rapidly and result in the multiple organ dysfunction syndrome. The leading role in this process is played by the Systemic Inflammatory Response that is accompanied by the production of pro- and anti-inflammatory cytokines, acute phase proteins, and reactive oxygen and nitrogen species.The purpose of this review that highlights both the recent reports and the results of the authors' own research is to encourage scientists to develop new approaches to the differentiated therapy of various SIR manifestations (low- and high-grade systemic inflammatory response phenotypes) by modulating redox-sensitive transcription factors with polyphenols and to evaluate the saturation of the pharmaceutical market with appropriate dosage forms tailored for targeted delivery of these compounds.Redox-sensitive transcription factors such as NFκB, STAT3, AP1 and Nrf2 have a leading role in mechanisms of the formation of low- and high-grade systemic inflammatory phenotypes as variants of SIR. These phenotypic variants underlie the pathogenesis of the most dangerous diseases of internal organs, endocrine and nervous systems, surgical pathologies, and post-traumatic disorders.The use of individual chemical compounds of the class of polyphenols, or their combinations can be an effective technology in the therapy of SIR. Administering natural polyphenols in oral dosage forms is very beneficial in the therapy and management of the number of diseases accompanied with low-grade systemic inflammatory phenotype. The therapy of diseases associated with high-grade systemic inflammatory phenotype requires medicinal phenol preparations manufactured for parenteral administration.

Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia–neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h—while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress. [ABSTRACT FROM AUTHOR]

Chronic venous disease (CVD) is an often underestimated inflammatory pathological condition that can have a serious impact on quality of life. Many therapies have been proposed to deal with CVD, but unfortunately the symptoms recur with increasing frequency and intensity as soon as treatments are stopped. Previous studies have shown that the common inflammatory transcription factor AP-1 (activator protein-1) and nuclear factor kappa-activated B-cell light chain enhancer (NF-kB) play key roles in the initiation and progression of this vascular dysfunction. The aim of this research was to develop a herbal product that acts simultaneously on different aspects of CVD-related inflammation. Based on the evidence that several natural components of plant origin are used to treat venous insufficiency and that magnolol has been suggested as a putative modulator of AP-1, two herbal preparations based on Ruscus aculeatus root extracts, and Vitis vinifera seed extracts, as well as diosmetin and magnolol, were established. A preliminary MTT-based evaluation of the possible cytotoxic effects of these preparations led to the selection of one of them, named DMRV-2, for further investigation. First, the anti-inflammatory efficacy of DMRV-2 was demonstrated by monitoring its ability to reduce cytokine secretion from endothelial cells subjected to LPS-induced inflammation. Furthermore, using a real-time PCR-based protocol, the effect of DMRV-2 on AP-1 expression and activity was also evaluated; the results obtained demonstrated that the incubation of the endothelial cells with this preparation almost completely nullified the effects exerted by the treatment with LPS on AP-1. Similar results were also obtained for NF-kB, whose activation was evaluated by monitoring its distribution between the cytosol and the nucleus of endothelial cells after the different treatments. [ABSTRACT FROM AUTHOR]

One of the major mysteries in science is how it is possible to pack the cellular chromatin with a total length of over 1 m, into a small sphere with a diameter of 5 mm “the nucleus”, and even more difficult to envisage how to make it functional. Although we know that compaction is achieved through the histones, however, the DNA needs to be accessible to the transcription machinery and this is allowed thanks to a variety of very complex epigenetic mechanisms. Either DNA (methylation) or post-translational modifications of histone proteins (acetylation, methylation, ubiquitination and sumoylation) play a crucial role in chromatin remodelling and consequently on gene expression. Recently the serotonylation and dopaminylation of the histone 3, catalyzed by the Transglutaminase type 2 (TG2), has been reported. These novel post-translational modifications catalyzed by a predominantly cytoplasmic enzyme opens a new avenue for future investigations on the enzyme function itself and for the possibility that other biological amines, substrate of TG2, can influence the genome regulation under peculiar cellular conditions. In this review we analyzed the nuclear TG2’s biology by discussing both its post-translational modification of various transcription factors and the implications of its epigenetic new face. Finally, we will focus on the potential impact of these events in human diseases. [ABSTRACT FROM AUTHOR]

Sepsis remains a worldwide public health problem. This study aims to explore the role and mechanism of transcriptional factors (TFs) in sepsis‐induced myocardial injury. Firstly, TF KLF13 was selected to explore its role in sepsis‐induced myocardial injury. The caecal ligation and puncture (CLP) ‐induced sepsis mouse model was established and the septic mice were examined using standard histopathological methods. KLF13 expression was detected in the septic mouse heart and was also seen in a lipoploysaccharide (LPS) ‐induced cellular inflammation model. To explore this further both pro‐apoptotic cleaved‐caspase3/caspase3 and Bax levels and anti‐apoptotic Bcl2 levels were examined, also in both models, In addition inflammatory cytokine (IL‐1β, TNF‐α, IL‐8 and MCP‐1) production and IκB‐α protein level and p65 phosphorylation were examined in both septic mice and LPS‐induced cells. Thus three parameters ‐ cardiomyocyte apoptosis, inflammatory response and NF‐κB pathway activation were evaluated under similar conditions. The septic mice showed significant oedema, disordered myofilament arrangement and degradation and necrosis to varying degrees in the myocardial cells. KLF13 was downregulated in both the septic mouse heart and the LPS‐induced cellular inflammation model. Furthermore, both models showed abnormally increased cardiomyocyte apoptosis (increased cleaved‐caspase3/caspase and Bax protein levels and decreased Bcl2 level), elevated inflammation (increased production of inflammatory cytokines) and the activated NF‐κB pathway (increased p65 phosphorylation and decreased IκB‐α protein level). KLF13 overexpression notably ameliorated sepsis‐induced myocardial injury in vivo and in vitro. KLF13 overexpression protected against sepsis‐induced myocardial injury and LPS‐induced cellular inflammation and apoptosis via inhibiting the inflammatory pathways (especially NF‐κB signalling) and cardiomyocyte apoptosis. [ABSTRACT FROM AUTHOR]

Maize developed from its ancestor, teosinte, about 10,000 years ago. The evolution has gone from teosinte with multiple tillers to single-tiller maize plants. An investigation took place to identify and sequence genes related to tillering ability in maize and perform In silico analysis. Mating proceeded by manual pollination between the commercial hybrid SC2031 of maize (Zea mays L.) and the teosinte genotype Domiata (Durra rayyana). The parents, F1 hybrids, and their F2 progenies gained evaluation for tillering ability. The SC2031 (low or no-tillers) exhibited fragments ranging from 75 to 420 bp. The fragment observed with 262 bp size was in the F1 and nine out of 10 low-tillering F2 progenies. The Domiata parent, a high-tillering variety, exhibited three fragments ranging from 82 to 534 bp. The fragment with 445 in size occurred in nine out of 10 high-tillering F2 progenies. The fragment of 262 bp, which may be responsible for the low tillering ability, and the fragment of 445 bp, for the high tillering ability, were eluted from the gel, sequenced, and submitted to GenBank. The predicted protein, T1-L, of the DNA sequence from the low-tillering parent has a molecular weight of 6.69 kD and pI of 6.53, belonging to the GRAS family, which plays an important role as transcriptional factors required for the adequate pattern of radial rooting and shooting. The predicted protein, T1-H, of the DNA sequence from the high-tillering parent has a molecular weight of 14.08 kD, and pI of 7.97, belonging to the TEOSINTE BRANCHED 1, CYCLOIDEA, PCF1 (TCP) family that plays an essential role as transcriptional factors required for apical dominance. [ABSTRACT FROM AUTHOR]

The present review highlights the growth and productivity of a rice crop that is an issue due to global climate change and Nitrogen deficiency that induce different stresses in a crop. Researchers reported a reduction in rice productivity due to drought stress worldwide. A comprehensive bioinformatics analysis, including Transcriptional Factors, was developed to analyze multi-omics data. Multi-omics technique provides a better understanding of cellular dynamics under many different kinds of stresses or either against biotic or abiotic stresses. The most important multi-omic techniques, Genomics, Proteomics, Transcriptomics and Metabolomics, have been recently studied. Breeding drought-tolerant rice varieties are more adaptive due to multigenic control of drought-tolerant traits. Drought significantly decreased agronomic traits, with biomass at 25.2% and yield at 25.4%. Nitrate Transporters play a critical role in nitrogen absorption. Nitrogen induces leaf production and expansion, shoots to root distance, accelerates transpiration and photosynthesis and promotes yield, especially under abiotic stresses in which drought is more effective. Plants use nitrogen as ammonium (NH₄+) and Nitrate (NO₃- ), which can affect various aspects of a plant. This review provides an extensive outline of breeding methods and mineral induction from conventional to the latest innovation in molecular development of drought-tolerant rice varieties. This information could serve as a guideline for researchers and rice breeders. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) represents the third most prevalent form of cancer, comprising approximately 7% of all cancer varieties. The primary objective of this study is to pinpoint and scrutinize the differentially expressed genes (DEGs) present in early-onset CRC (EOCRC) as compared to late-onset CRC (LOCRC). For our analysis, we retrieved RNA-seq data from the GEO database, subsequently employing the GEO2R tool for its evaluation. This step was followed by an extensive process of gene and pathway enrichment, identification of protein-protein interactions, and the prediction of pivotal transcriptional factors. Additionally, we examined survival rates and responses to chemotherapy treatments. We identified 250 DEGs, of which 235 were down-regulated and 15 were up-regulated. The most prevalent categories identified were extracellular structure organization in biological processes, collagen-containing extracellular matrix in cellular compartments, platelet-derived growth factor in molecular functions, and protein digestion and absorption in KEGG pathways. Furthermore, we isolated ten central hub genes: COL1A1, VWF, COL3A1, EGF, IGF1, COL1A2, ITGB3, COL11A2, COL6A1, and CD163. Among these, COL1A1 and EGF stand out; COL1A1 serves as a predictive biomarker, while EGF holds potential as a prognostic biomarker. Additionally, our predictive models highlight FOXC1, GATA2, YY1, TFAP2A, and PPARG as the most influential transcriptional factors governing these hub genes. In summation, our findings suggest that these hub genes play a crucial role in differentiating EOCRC from LOCRC, warranting further comprehensive investigation.

Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte–neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer's disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) possess the potential to differentiate into chondrocytes, which makes them an ideal source for healing cartilage defects. Here, we seek to identify the essential genes participating in MSCs chondrogenesis.Methods: Human MSCs were induced for chondrogenesis for 7, 14, and 21 days using a high-density micromass culture system, and RNA was extracted for RNA-seq.Results: A total of 6247 differentially expressed genes (DEGs) were identified on day 7, and 85 DEGs were identified on day 14. However, no significant DEGs was identified on day 21. The top 30 DEGs at day 7, including COL9A3, COL10A1, and CILP2, are closely related to extracellular matrix organization. While the top 30 DEGs at day 14 revealed that inflammation-related genes were enriched, including CXCL8, TLR2, and CCL20. We also conducted protein-protein interaction (PPI) networks analysis using the search tool for the retrieval of interacting genes (STRING) database and identified key hub genes, including CXCL8, TLR2, CCL20, and MMP3. The transcriptional factors were also analyzed, identifying the top 5 TFs: LEF1, FOXO1, RORA, BHLHE41, and SOX5. We demonstrated one particular TF, RORA, in promoting early MSCs chondrogenesis.Conclusions: Taken together, our results suggested that these DEGs may have a complex effect on MSCs chondrogenesis both synergistically and solitarily. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy (DN) is a chronic microvascular complication in patients with diabetes mellitus, which is the leading cause of end-stage renal disease. However, the role of copper-related genes (CRGs) in DN development remains unclear. Materials and methods: CRGs were acquired from the GeneCards and NCBI databases. Based on the GSE96804 and GSE111154 datasets from the GEO repository, we identified hub CRGs for DN progression by taking the intersection of differentially expressed CRGs (DECRGs) and genes in the key module from Weighted Gene Co-expression Network Analysis. The Maximal Clique Centrality algorithm was used to identify the key CRGs from hub CRGs. Transcriptional factors (TFs) and microRNAs (miRNAs) targeting hub CRGs were acquired from publicly available databases. The CIBERSORT algorithm was used to perform comparative immune cell infiltration analysis between normal and DN samples. Results: Eighty-two DECRGs were identified between normal and DN samples, as were 10 hub CRGs, namely PTGS2, DUSP1, JUN, FOS, S100A8, S100A12, NAIP, CLEC4E, CXCR1, and CXCR2. Thirty-nine TFs and 165 miRNAs potentially targeted these 10 hub CRGs. PTGS2 was identified as the key CRG and FOS as the most significant gene among all of DECRGs. RELA was identified as the hub TF interacting with PTGS2 by taking the intersection of potential TFs from the ChEA and JASPAR public databases. let-7b-5p was identified as the hub miRNA targeting PTGS2 by taking the intersection of miRNAs from the miRwalk, RNA22, RNAInter, TargetMiner, miRTarBase, and ENCORI databases. Similarly, CREB1, E2F1, and RELA were revealed as hub TFs for FOS, and miR-338-3p as the hub miRNA. Finally, compared with those in healthy samples, there are more infiltrating memory B cells, M1 macrophages, M2 macrophages, and resting mast cells and fewer infiltrating activated mast cells and neutrophils in DN samples (all p< 0.05). Conclusion: The 10 identified hub copper-related genes provide insight into the mechanisms of DN development. It is beneficial to examine and understand the interaction between hub CRGs and potential regulatory molecules in DN. This knowledge may provide a novel theoretical foundation for the development of diagnostic biomarkers and copper-related therapy targets in DN. [ABSTRACT FROM AUTHOR]

Soybean plant architecture has a significant impact on yield potential, but the genetic underpinnings of key architectural traits remain elusive. The primary objective of this study was to explore the genetic foundations underlying main stem node number (MSN) in soybeans. Recombinant inbred lines (RILs) contained a 234 individual derived from crosses between two cultivars Zhonghuang35 (ZH35) and Jindou21 (JD21) was evaluated for seed hardness across 3 years (2013, 2014, and 2015 in Gansu). Markedly, the parent varieties, shown significant differences in MSN. Also, the RIL population exhibited a wide range of genetic variation in MSN. A high-density genetic map composed of 8,078 specific-locus amplified fragment (SLAF) markers, spanning 3,480.98 centimorgans (cM) with an average inter-marker distance of 0.59 cM were used to construct linkage map. Using ICIM analysis identified a total of 23 Quantitative Trait Loci (QTLs) across the 20 chromosome, of which five QTLs were detected in multiple years in Chr.6. Notably, we identified a stable major QTL, qMSN-6-4 , explaining up to 24.81% of phenotypic variation. This QTL govern seven candidate genes with potential roles in regulating MSN development in soybean, including Glyma.06G027500 with a domain of unknown function, Glyma.06G027600 involved in proton transport, Glyma.06G027700 linked to proteolysis, Glyma.06G027900 related to transcriptional regulation, and Glyma.06G028000 and Glyma.06G028050 associated with membrane functions. The RT-PCR analysis confirmed that these genes were expressed differently between the parental lines this supports the idea that they may play a role in determining MSN. Glyma.06G027500 and Glyma.06G027600 showing higher expression in JD21 leaves and nodes, while Glyma.06G027700 and Glyma.06G028000 exhibited increased expression in ZH35 stems, highlighting their distinct roles in transcription regulation, membrane activities, and protein degradation that contribute to MSN formation in soybean. This study offers valuable insights into the genetic mechanisms governing soybean MSN, providing a foundation for future research and crop improvement efforts., Competing Interests: The authors declare that they have no competing interests., (© 2024 Ren et al.)

Objective: The current research was aimed to identify candidate genes associated with development and progression of epithelial ovarian carcinoma using bioinformatics analysis. Materials and methods: We screened and validated candidate genes associated with carcinogenesis and development of epithelial ovarian carcinoma via bioinformatic analysis in three microarray datasets (GSE14407, GSE29450, and GSE54388) downloaded from the Gene Expression Omnibus (GEO) database. Results: Our bioinformatic analysis identified 514 differentially expressed genes (DEGs) and nine candidate hub genes (CCNB1, CDK1, BUB1, CDC20, CCNA2, BUB1B, AURKA, RRM2, and TTK). Survival analysis using the Kaplan–Meier plotter showed that high expression levels of seven candidate genes (CCNB1, RRM2, BUB1, CCNA2, AURKA, CDK1, and BUB1B) were associated with poor overall survival (OS). Gene Expression Profiling Interactive Analysis (GEPIA) revealed a higher expression level of these seven candidate genes in ovarian carcinoma samples than in normal ovarian samples. Immunostaining results from the Human Protein Atlas (HPA) database suggested that the protein expression levels of CCNB1, CCNA2, AURKA, and CDK1 were increased in ovarian cancer tissues. No difference was observed in RRM2 protein expression level between normal ovarian and ovarian cancer samples. Oncomine analysis revealed an association between the expression patterns of BUB1B, CCNA2, AURKA, CCNB1, CDK1, and BUB1 and patient clinicopathological information. Finally, six genes, namely CCNB1, CCNA2, AURKA, BUB1, BUB1B, and CDK1, were identified as hub genes and a transcription factor (TF)-gene regulatory network was constructed to identify TFs, including POLR2A, ZBTB11, KLF9, and ELF1, that were implicated in regulating these hub genes. Conclusion: Six significant hub DEGs associated with a poor prognosis in epithelial ovarian cancer were identified. These could be potential biomarkers for ovarian cancer patients.

Transposable elements (TEs) and transcription factors (TFs) are involved in the precise regulation of gene expression during the preimplantation stage. Activation of TEs is a key event for mammalian embryonic genome activation and preimplantation early embryonic development. TFs are involved in the regulation of drastic changes in gene expression patterns, but an inventory of the interplay between TEs and TFs during normal/abnormal human embryonic development is still lacking. Here we used single-cell RNA sequencing data generated from biparental and uniparental embryos to perform an integrative analysis of TE and TF expression. Our results showed that endogenous retroviruses (ERVs) are mainly expressed during the minor embryonic genome activation (EGA) process of early embryos, while Alu is gradually expressed in the middle and later stages. Some important ERVs (e.g., LTR5_Hs, MLT2A1) and Alu TEs are expressed at significantly lower levels in androgenic embryos. Integrative analysis revealed that the expression of the transcription factors CTCF and POU5F1 is correlated with the differential expression of ERV TEs. Comparative coexpression network analysis further showed distinct expression levels of important TFs (e.g., LEUTX and ZSCAN5A) in dizygotic embryos vs. parthenogenetic and androgenic embryos. This systematic investigation of TE and TF expression in human early embryonic development by single-cell RNA sequencing provides valuable insights into mammalian embryonic development.

Circulating free-cell miRNAs are increasingly important as potential non-invasive biomarkers due to the easy accessibility of clinical materials. Moreover, their epigenetic role may provide insight into the mechanisms of pathogenesis. Nevertheless, these aspects are mostly studied in the area of oncological diseases. Therefore, this research aimed to find the potential association of selected miRNAs in serum with the expression of Th17/Treg transcription factors and clinical features in RA patients. Accordingly, experiments was conducted on rheumatoid arthritis (RA), osteoarthritis (OA) and healthy subjects (HC). Analysis of miRNAs level in serum was performed using LNA miRNA PCR assays. mir-10 was detected only in RA patients. Furthermore, its expression was correlated with IL-35 serum concentration and the mRNA level of STAT5a in whole blood in RA. Additionally, a tendency of the raised level of miR-10 was noted in RA patients with high activity disease. miR-326 was significantly upregulated in RA patients with rheumatoid factor presence. In HC the correlation between miR-26 and IL-21 serum levels and expression of SMAD3 have been found. In OA patients, correlations between miR-126 and HIF1 expression and between miR-146 and RORc have been noted. The differential association of transcription factor expression with serum miRNA levels may be important in the diagnosis and progression of RA and OA. [ABSTRACT FROM AUTHOR]

Abstract Background Isatidis Radix, the root of Isatis indigotica Fort. (Chinese woad) can produce a variety of efficacious compound with medicinal properties. The tetraploid I. indigotica plants exhibit superior phenotypic traits, such as greater yield, higher bioactive compounds accumulation and enhanced stress tolerance. In this study, a comparative transcriptomic and metabolomic study on Isatidis Radix autotetraploid and its progenitor was performed. Results Through the targeted metabolic profiling, 283 metabolites were identified in Isatidis Radix, and 70 polyploidization-altered metabolites were obtained. Moreover, the production of lignans was significantly increased post polyploidization, which implied that polyploidization-modulated changes in lignan biosynthesis. Regarding the transcriptomic shift, 2065 differentially expressed genes (DEGs) were identified as being polyploidy-responsive genes, and the polyploidization-altered DEGs were enriched in phenylpropanoid biosynthesis and plant hormone signal transduction. The further integrative analysis of polyploidy-responsive metabolome and transcriptome showed that 1584 DEGs were highly correlated with the 70 polyploidization-altered metabolites, and the transcriptional factors TFs-lignans network highlighted 10 polyploidy-altered TFs and 17 fluctuated phenylpropanoid pathway compounds. Conclusions These results collectively indicated that polyploidization contributed to the high content of active compounds in autotetraploid roots, and the gene–lignan pathway network analysis highlighted polyploidy–responsive key functional genes and regulators.

Abstract Background Recent evidences indicated that shear stress is critical in orchestrating gene expression in cardiovascular disease. It is necessary to identify the mechanism of shear stress influencing gene expression in physiology and pathophysiology conditions. This paper aimed to identify candidate hub genes and its transcription factors with bioinformatics. Methods We analyzed microarray expression profile of GSE16706 to identify differentially expressed genes (DEGs) in low shear stress (1 dyne/cm2) treated human umbilical vein endothelial cells (HUVECs) compared with static condition for 24 h. Results 652 DEGs, including 333 up-regulated and 319 down-regulated DEGs, were screen out. Functional enrichment analysis indicated enrichment items mainly included cytokine-cytokine receptor interaction and cell cycle. Five hub genes (CDC20, CCNA2, KIF11, KIF2C and PLK1) and one significant module (score = 17.39) were identified through protein–protein interaction (PPI) analysis. Key transcriptional factor FOXC1 displayed close interaction with all the hub genes via gene-transcriptional factor network. Single-gene GSEA analysis indicated that CDC20 was linked to the G2M_CHECKPOINT pathway and cell cycle pathway. Conclusions By using integrated bioinformatic analysis, a new transcriptional factor and hub-genes network related to HUVECs treated with low shear stress were identified. The new regulation mechanism we discovered may be a promising potential therapeutic target for cardiovascular disease.

Rhizobium giardinii has been demonstrated to colonize the roots of a variety of legume species, including common beans, and to increase nitrogen fixation. This suggests that Rhizobium giardinii might be a beneficial tool for sustainable agriculture by lowering dependency on synthetic nitrogen fertilizers and enhancing soil fertility. Understanding the regulatory components in the R. giardinii A3AY_RS01 genes might also lead to the creation of innovative ways for increasing the effectiveness of nitrogen fixation in other agriculturally important bacteria. Therefore, this study was aimed to predict regulatory element of R. giardinii DNA-binding response regulator A3AY_RS01 genes. The locations for 19 % of the Transcriptional start site (TSSs) were within − 300 bp relative to the start codon and ten candidate motifs were identified that are shared by at least 50 % of the R. giardinii A3AY_RS01 promoter input sequences from both strands. Motif 1 was revealed as the common promoter motif for all of R. giardinii A3AY_RS01 genes that serves as binding sites for TFs involved in the expression regulation of these genes. Hence, it was revealed that Motif 1 may serve as the binding site chiefly for Ferric uptake regulator (Fur) transcription factor family to regulate expression of A3AY_RS01 genes. High CpG density in the promoter than body regions were observed for most of the genes except for A3AY_RS0102950, A3AY_RS0120195 and A3AY_RS0131150 genes. Nonetheless, promoter areas were richer than body regions in both techniques. MV1 motif can serve as a binding site for the Fur transcription factor gene family in R. giardinii to regulate the expression of R. giardinii A3AY_RS01 genes. R. giardinii A3AY_RS01 genes are rich in CpG Islands, and play an important role in the regulation of the gene expression of nitrogen fixing in this bacterium. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) and coronary heart disease (CHD) stand as two of the foremost causes of mortality. However, the comprehensive comprehension of the regulatory mechanisms governing DCM and CHD remains limited, particularly from the vantage point of single-cell transcriptional analysis. We used the GSE121893 dataset from the GEO database, analyzing single-cell expressions with tools like DropletUtils, Seurat, and Monocle. We also utilized the GSVA package for comparing gene roles in DCM and CHD, Finally, we conducted qRT-PCR and Western blot analyses to measure the expression levels of SMARCA4, Col1A1, Col3A1 and α-SMA, and the role of SMARCA4 on fibroblasts were explored by EdU and Transwell assay. Our analysis identified six cell types in heart tissue, with fibroblasts showing the most interaction with other cells. DEGs in fibroblasts were linked to muscle development and morphogenesis. Pseudotime analysis revealed the dynamics of fibroblast changes in both the normal and disease groups and many transcription factors (TFs) potentially involved in this process. Among these TFs, SMARCA4 which was translated into protein BRG1, showed the most significantly difference. In vivo experiments have demonstrated that SMARCA4 indeed promoted fibroblasts proliferation and migration. This study provides a clearer understanding of cell-type dynamics in heart diseases, emphasizing the role of fibroblasts and the significance of SMARCA4 in their function. Our results offer insights into the cellular mechanisms underlying DCM and CHD, potentially guiding future therapeutic strategies. • This study explores the regulatory mechanisms governing Dilated Cardiomyopathy (DCM) and Coronary Heart Disease (CHD) using single-cell transcriptional analysis. • The GSE121893 dataset from the GEO database was utilized, and tools like DropletUtils, Seurat, Monocle, and GSVA package were employed for analysis. • Fibroblasts were identified as a crucial cell type with significant interactions in heart tissue, and their dynamics in both normal and disease groups were revealed through pseudotime analysis. • SMARCA4, translated into protein BRG1, showed significant differences and was found to promote fibroblast proliferation and migration in in vivo experiments. • This study enhances the understanding of cell-type dynamics in heart diseases, highlighting the role of fibroblasts and the significance of SMARCA4. • The findings provide insights into the cellular mechanisms underlying DCM and CHD, potentially guiding future therapeutic strategies. [ABSTRACT FROM AUTHOR]