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Temperature-dependent alternative splicing (AS) is a crucial mechanism for organisms to adapt to varying environmental temperatures. In mammals, even slight fluctuations in body temperature are sufficient to drive significant AS changes in a concerted manner. This dynamic regulation allows organisms to finely tune gene expression and protein isoform diversity in response to temperature cues, ensuring proper cellular function and physiological adaptation. Understanding the molecular mechanisms underlying temperature-dependent AS thus provides valuable insights into the intricate interplay between environmental stimuli and gene expression regulation. In this review, we provide an overview of recent advances in understanding temperature-regulated AS across various biological processes and systems. We will discuss the machinery sensing and translating temperature cues into changed AS patterns, the adaptation of the splicing regulatory machinery to extreme temperatures, the role of temperature-dependent AS in shaping the transcriptome, functional implications and the development of potential therapeutics targeting temperature-sensitive AS pathways. [ABSTRACT FROM AUTHOR]

Background: The specific role of oxidative stress (OS) in vitiligo and alopecia areata (AA) remains unclear. The aim of this study was to analyze and identify the key markers of OS in vitiligo and AA by bioinformatics. Methods: We obtained vitiligo and AA datasets from gene expression omnibus (GEO) database. The difference‐expressed genes of vitiligo and AA were identified by differential analysis, and the functions of difference‐expressed genes were identified by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis. Subsequently, Veen package was used to obtain the intersection genes of OS‐related genes with vitiligo and AA. Finally, we used CIBERSORT to assess the infiltration of immune cells in vitiligo and AA. Results: Through enrichment analysis, we found that vitiligo and AA were mainly enriched in cell cycle and cell adhesion molecular channels. We identified KLB and EIF3C as key genes in OS regulation of vitiligo and AA, and found that KLB and EIF3C participate in disease progression by regulating T cells and neutrophils. Conclusions: According to our findings, KLB and EIF3C play a crucial role in the progression and development of vitiligo and AA, which have been identified as biomarkers and target for early diagnosis of patients. [ABSTRACT FROM AUTHOR]

The inflammatory response is tightly regulated to eliminate invading pathogens and avoid excessive production of inflammatory mediators and tissue damage. Caspase‐8 is a cysteine protease that is involved in programmed cell death. Here we show the TRIF‐RIPK1‐Caspase‐8 is required for LPS‐induced CYLD degradation in macrophages. TRIF functions in the upstream of RIPK1. The homotypic interaction motif of TRIF and the death domain of RIPK1 are essential for Caspase‐8 activation. Caspase‐8 cleaves CYLD and the D235A mutant is resistant to the protease activity of Caspase‐8. TRIF and RIPK1 serve as substrates of Capase‐8 in vitro. cFLIP interacts with Caspase‐8 to modulate its protease activity on CYLD and cell death. Deficiency in TRIF, Caspase‐8 or CYLD can lead to a decrease or increase in the expression of genes encoding inflammatory cytokines. Together, the TRIF‐Caspase‐8 and CYLD play opposite roles in the regulation of TLR4 signalling. [ABSTRACT FROM AUTHOR]

Since the molecular mechanisms behind adaptation and the bacterial stress response toward antimicrobial photodynamic therapy (aPDT) are not entirely clear yet, the aim of the present study was to investigate the transcriptomic stress response in Escherichia coli after sublethal treatment with aPDT using RNA sequencing (RNA-Seq). Planktonic cultures of stationary phase E. coli were treated with aPDT using a sublethal dose of the photosensitizer SAPYR. After treatment, RNA was extracted, and RNA-Seq was performed on the Illumina NextSeq 500. Differentially expressed genes were analyzed and validated by qRT-PCR. Furthermore, expression of specific stress response proteins was investigated using Western blot analysis.The analysis of the differential gene expression following pathway enrichment analysis revealed a considerable number of genes and pathways significantly up- or down-regulated in E. coli after sublethal treatment with aPDT. Expression of 1018 genes was up-regulated and of 648 genes was down-regulated after sublethal treatment with aPDT as compared to irradiated controls. Analysis of differentially expressed genes and significantly de-regulated pathways showed regulation of genes involved in oxidative stress response and bacterial membrane damage. In conclusion, the results show a transcriptomic stress response in E. coli upon exposure to aPDT using SAPYR and give an insight into potential molecular mechanisms that may result in development of adaptation. [ABSTRACT FROM AUTHOR]

• MicroRNA-mediated gene regulation enables plant adaptation and survival under stressors like drought, salinity, heat, and heavy metals. • Addressing this biological importance a computational model has developed for identification of MiRNA and Pre-MiRNA based on RNA sequences. • The relative positioning based feature vector has been computed with ensemble modeling for classification purpose. • The proposed study overcome the existing studies by enhancing the accuracy of computational model. • The webservers for identification of MiRNA and Pre-MiRNA has been developed. This study proposed an intelligent model for predicting abiotic stress-responsive microRNAs in plants. MicroRNAs (miRNAs) are short RNA molecules regulates the stress in genes. Experimental methods are costly and time-consuming, as compare to in-silico prediction. Addressing this gap, the study seeks to develop an efficient computational model for plant stress response prediction. The two benchmark datasets for MiRNA and Pre-MiRNA dataset have been acquired in this study. Four ensemble approaches such as bagging, boosting, stacking, and blending have been employed. Classifiers such as Random Forest (RF), Extra Trees (ET), Ada Boost (ADB), Light Gradient Boosting Machine (LGBM), and Support Vector Machine (SVM). Stacking and Blending employed all stated classifiers as base learners and Logistic Regression (LR) as Meta Classifier. There have been a total of four types of testing used, including independent set, self-consistency, cross-validation with 5 and 10 folds, and jackknife. This study has utilized evaluation metrics such as accuracy score, specificity, sensitivity, Mathew's correlation coefficient (MCC), and AUC. Our proposed methodology has outperformed existing state of the art study in both datasets based on independent set testing. The SVM-based approach has exhibited accuracy score of 0.659 for the MiRNA dataset, which is better than the previous study. The ET classifier has surpassed the accuracy of Pre-MiRNA dataset as compared to the existing benchmark study, achieving an impressive score of 0.67. The proposed method can be used in future research to predict abiotic stresses in plants. [ABSTRACT FROM AUTHOR]

This article presents a study on the distribution of cytochrome P450 (CYP450) alleles in the Danish population. CYP450 enzymes are important for drug metabolism, and genetic variations in the genes encoding these enzymes can impact drug response. The study compared genotype data from different genotyping platforms and found that the CYP2C19*17 and CYP2C9*2 alleles were more common than the CYP2C19*2 and CYP2C9*3 alleles. The results provide valuable insights into the genetic variability of these enzymes in the Danish population and suggest that the Illumina GSA platform could be useful for identifying drug-gene interactions. [Extracted from the article]

Buckwheat (Fagopyrum spp.) is an underutilized resilient crop of North Western Himalayas belonging to the family Polygonaceae and is a source of essential nutrients and therapeutics. Common Buckwheat and Tatary Buckwheat are the two main cultivated species used as food. It is the only grain crop possessing rutin, an important metabolite with high nutraceutical potential. Due to its inherent tolerance to various biotic and abiotic stresses and a short life cycle, Buckwheat has been proposed as a model crop plant. Nutritional security is one of the major concerns, breeding for a nutrient-dense crop such as Buckwheat will provide a sustainable solution. Efforts toward improving Buckwheat for nutrition and yield are limited due to the lack of available: genetic resources, genomics, transcriptomics and metabolomics. In order to harness the agricultural importance of Buckwheat, an integrated breeding and OMICS platforms needs to be established that can pave the way for a better understanding of crop biology and developing commercial varieties. This, coupled with the availability of the genome sequences of both Buckwheat species in the public domain, should facilitate the identification of alleles/QTLs and candidate genes. There is a need to further our understanding of the molecular basis of the genetic regulation that controls various economically important traits. The present review focuses on: the food and nutritional importance of Buckwheat, its various omics resources, utilization of omics approaches in understanding Buckwheat biology and, finally, how an integrated platform of breeding and omics will help in developing commercially high yielding nutrient rich cultivars in Buckwheat. [ABSTRACT FROM AUTHOR]

Virus-encoded microRNAs (miRNAs) exert diverse regulatory roles in the biological processes of both viruses and hosts. This study delves into the functions of AcMNPV-miR-2, an early miRNA encoded by Autographa californica multiple nucleopolyhedrovirus (AcMNPV). AcMNPV-miR-2 targets viral early genes ac28 (lef-6), ac37 (lef-11), ac49, and ac63. Overexpression of AcMNPV-miR-2 leads to reduced production of infectious budded virions (BVs) and diminished viral DNA replication. Delayed polyhedron formation was observed through light and transmission electron microscopy, and the larval lifespan extended in oral infection assays. Moreover, the mRNA expression levels of two Lepidoptera-specific immune-related proteins, Gloverin and Spod-11-tox, significantly decreased. These findings indicate that AcMNPV-miR-2 restrains viral load, reducing host immune sensitivity. This beneficial effect enables the virus to combat host defense mechanisms and reside within the host for an extended duration. IMPORTANCE Virus-encoded miRNAs have been extensively studied for their pivotal roles in finetuning viral infections. Baculoviruses, highly pathogenic in insects, remain underexplored concerning their encoded miRNAs. Previous reports outlined three AcMNPV-encoded miRNAs, AcMNPV-miR-1, -miR-3, and -miR-4. This study delves into the functions of another AcMNPV-encoded miRNA, AcMNPV-miR-2 (Ac-miR-2). Through a comprehensive analysis of target gene expression, the impact on larvae, and variations in host immune-related gene expression, we elucidate a functional pathway for Ac-miR-2. This miRNA suppresses viral load and infectivity and prolongs lifespans of infected larva by downregulating specific viral early genes and host immune-related genes. These mechanisms ultimately serve the virus's primary goal of enhanced propagation. Our study significantly contributes to understanding of the intricate regulatory mechanisms of virus-encoded miRNAs in baculovirus infections. [ABSTRACT FROM AUTHOR]

Kaposi’s sarcoma herpesvirus (KSHV) ORF34 plays a significant role as a component of the viral pre-initiation complex (vPIC), which is indispensable for late gene expression across beta- and gammaherpesviruses. Although the key role of ORF34 within the vPIC and its function as a hub protein have been recognized, further clarification regarding its specific contribution to vPIC functionality and interactions with other components is required. This study employed a deep learning algorithm-assisted structural model of ORF34, revealing highly conserved amino acid residues across human beta- and gammaherpesviruses localized in structured domains. Thus, we engineered ORF34 alanine-scanning mutants by substituting conserved residues with alanine. These mutants were evaluated for their ability to interact with other vPIC factors and restore viral production in cells harboring the ORF34-deficient KSHV-BAC. Our experimental results highlight the crucial role of the four cysteine residues conserved in ORF34: a tetrahedral arrangement consisting of a pair of C-Xn-C consensus motifs. This suggests the potential incorporation of metal cations in interacting with ORF24 and ORF66 vPIC components, facilitating late gene transcription, and promoting overall virus production by capturing metal cations. In summary, our findings underline the essential role of conserved cysteines in KSHV ORF34 for effective vPIC assembly and viral replication, thereby enhancing our understanding of the complex interplay between the vPIC components. IMPORTANCE The initiation of late gene transcription is universally conserved across the beta- and gammaherpesvirus families. This process employs a viral pre-initiation complex (vPIC), which is analogous to a cellular PIC. Although KSHV ORF34 is a critical factor for viral replication and is a component of the vPIC, the specifics of vPIC formation and the essential domains crucial for its function remain unclear. Structural predictions suggest that the four conserved cysteines (C170, C175, C256, and C259) form a tetrahedron that coordinates the metal cation. We investigated the role of these conserved amino acids in interactions with other vPIC components, late gene expression, and virus production to demonstrate for the first time that these cysteines are pivotal for such functions. This discovery not only deepens our comprehensive understanding of ORF34 and vPIC dynamics but also lays the groundwork for more detailed studies on herpesvirus replication mechanisms in future research. [ABSTRACT FROM AUTHOR]

Plant transcription factors are evolutionarily conserved proteins that play an important role in the transcriptional regulation of gene expression by binding to their specific DNA sequences. BSD (mammalian BTF2-like transcription factors, synapse-associated proteins, and DOS2-like proteins) transcription factors are conserved in various species, from protozoa to humans, and are characterized by a typical BSD domain. However, little information is available about their possible roles in plant growth and development, and to date, members of this transcription factor family have not been systematically identified and analyzed in apricot. In this study, two BSD domain-encoding genes were identified in the apricot genome. Expression profile analysis by RT-qPCR revealed that both genes participate in different developmental stages of three different organs in apricot. PaBSD1 was expressed higher than PaBSD2 only in the stamen. Moreover, PaBSD2 was higher expressed than PaBSD1 in four different fruit stages, young leaf, leaf bud, sepal and petal. This study reveals the critical roles of BSD transcription factors in apricot development, with PaBSD1 showing higher expression in stamen and PaBSD2 in various fruit stages and leaf tissues. These findings provide a foundation for future functional studies and apricot breeding programs. [ABSTRACT FROM AUTHOR]

The genomes and annotated genes of allotetraploid cotton Gossypium hirsutum have been extensively studied in recent years. However, the expression, regulation, and evolution of intergenic genes (ITGs) have not been completely deciphered. In this study, we identified a novel set of actively expressed ITGs in G. hirsutum cotton, through transcriptome profiling based on deep sequencing data, as well as chromatin immunoprecipitation, followed by sequencing (ChIP-seq) of histone modifications and how the ITGs evolved. Totals of 17,567 and 8249 ITGs were identified in G. hirsutum and Gossypium arboreum, respectively. The expression of ITGs in G. hirsutum was significantly higher than that in G. arboreum. Moreover, longer exons were observed in G. hirsutum ITGs. Notably, 42.3% of the ITGs from G. hirsutum were generated by the long terminal repeat (LTR) insertions, while their proportion in genic genes was 19.9%. The H3K27ac and H3K4me3 modification proportions and intensities of ITGs were equivalent to genic genes. The H3K4me1 modifications were lower in ITGs. Additionally, evolution analyses revealed that the ITGs from G. hirsutum were mainly produced around 6.6 and 1.6 million years ago (Mya), later than the pegged time for genic genes, which is 7.0 Mya. The characterization of ITGs helps to elucidate the evolution of cotton genomes and shed more light on their biological functions in the transcriptional regulation of eukaryotic genes, along with the roles of histone modifications in speciation and diversification. [ABSTRACT FROM AUTHOR]

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-b expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-b induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-b, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-b mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-b via mitochondrial dsDNA release. [ABSTRACT FROM AUTHOR]

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity. The cardiac conduction system consists of specialized cardiomyocytes that synchronize heart contractions. Here, Oh et al. provide comprehensive molecular profiles of the postnatal cardiac conduction system and elucidate gene regulatory mechanisms contributing to its heterogeneity. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts – including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 – associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology. The authors used long-read sequencing to reveal novel isoforms and differential transcript use in a transgenic model of tau pathology. Similar patterns were found in the human cortex, supporting a role for alternative splicing in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Polyhalogenated carbazoles (PHCZs) are a class of nitrogen-containing heterocyclic compounds that are widely distributed throughout the marine environment and sediment. These compounds share structural and toxicity similarities with dioxins. However, our understanding of the toxicological effects of PHCZs on marine organisms and their underlying molecular mechanisms remains limited. In this study, we employed the marine model organism Mugilogobius chulae as the experimental subject and selected 2,7-dibromocarbazole (2,7-DBCZ), a compound known for its high toxicity and detection frequency, to conduct both an acute toxicity test and transcriptome analysis on M. chulae embryos. Our findings revealed that the 96 h median lethal concentration (LC50) of 2,7-DBCZ for M. chulae embryos was 174 μg/L, with a median effective concentration (EC50) resulting in pericardial edema deformity of 88.82 μg/L. Transcriptome analysis revealed significant impacts on various systems in M. chulae embryos following exposure to 2,7-DBCZ, including the sensory, cardiovascular, immune, and endocrine systems. Furthermore, this compound perturbed signaling pathways such as phototransduction, protein folding and processing, amino acid metabolism, lipid transport, and exogenous compound metabolism. Notably, transcript abundance of the CYP1A gene associated with the activation of the AhR signaling pathway, similar to dioxin-like compounds, was 18.18 times higher than that in the control group. This observation suggests that M. chulae embryos mount a stress response when exposed to PHCZs. In summary, this study contributes to our understanding of the toxicological implications of PHCZ in marine fish and offers a theoretical foundation for risk assessment and regulatory frameworks for PHCZs in the marine environment. [ABSTRACT FROM AUTHOR]

Deuterium-depleted water (DDW) is used in the treatment of many diseases, including cancer and diabetes. To detect the effect of DDW on gene expression and activation of the insulin-responsive transporter GLUT4 as a mechanism for improving the pathology of diabetes, we investigated the GLUT4 expression and glucose uptake at various concentrations of DDW using the myoblast cell line C2C12 differentiated into myotubes. GLUT4 gene expression significantly increased under deuterium depletion, reaching a maximum value at a deuterium concentration of approximately 50 ppm, which was approximately nine times that of natural water with a deuterium concentration of 150 ppm. GLUT4 protein also showed an increase at similar DDW concentrations. The membrane translocation of GLUT4 by insulin stimulation reached a maximum value at a deuterium concentration of approximately 50–75 ppm, which was approximately 2.2 times that in natural water. Accordingly, glucose uptake also increased by up to 2.2 times at a deuterium concentration of approximately 50 ppm. Drug-induced insulin resistance was attenuated, and the glucose uptake was four times higher in the presence of 10 ng/mL TNF-α and three times higher in the presence of 1 μg/mL resistin at a deuterium concentration of approximately 50 ppm relative to natural water. These results suggest that DDW promotes GLUT4 expression and insulin-stimulated activation in muscle cells and reduces insulin resistance, making it an effective treatment for diabetes. [ABSTRACT FROM AUTHOR]

In this focused genetic case–control study, we analyzed two functional single-nucleotide variants (SNVs) associated with breast cancer risk (rs2046210, rs9383590) and one risk SNV for an implantation defect and infertility (rs9340799) for their association with endometriosis susceptibility, progression and ESR1 gene regulation in endometriosis patients. The rs2046210, rs9383590 and rs9340799 SNVs were genotyped in 153 endometriosis patients and 87 control subjects with Caucasian ancestry. We analyzed the association of all SNVs with endometriosis susceptibility in all patients and in subgroups and assessed the concordance between the SNVs. Quantitative reverse transcription PCR was used to determine ESR1 gene expression in the eutopic endometrial tissue of the controls and endometriosis patients. The heterozygous rs2046210 GA genotype was associated with significantly increased endometriosis risk, particularly in younger, leaner and infertile women and with an increased ESR1 gene expression in the eutopic endometrium of these patients, compared to controls. The minor AA genotype of rs2046210 was identified as a potential risk factor for endometriosis progression in women with mild endometriosis. The results from this analysis indicate that rs2046210 may be a functional genetic variant associated with endometriosis development and progression. [ABSTRACT FROM AUTHOR]

Obesity is a multifactorial chronic inflammatory metabolic disorder, with pathogenesis influenced by genetic and non-genetic factors such as environment and diet. Intestinal microbes and their metabolites play significant roles in the occurrence and development of obesity by regulating energy metabolism, inducing chronic inflammation, and impacting intestinal hormone secretion. Epigenetics, which involves the regulation of host gene expression without changing the nucleotide sequence, provides an exact direction for us to understand how the environment, lifestyle factors, and other risk factors contribute to obesity. DNA methylation, as the most common epigenetic modification, is involved in the pathogenesis of various metabolic diseases. The epigenetic modification of the host is induced or regulated by the intestinal microbiota and their metabolites, linking the dynamic interaction between the microbiota and the host genome. In this review, we examined recent advancements in research, focusing on the involvement of intestinal microbiota and DNA methylation in the etiology and progression of obesity, as well as potential interactions between the two factors, providing novel perspectives and avenues for further elucidating the pathogenesis, prevention, and treatment of obesity. [ABSTRACT FROM AUTHOR]

The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high-level HLA-C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD-like receptor (NLR) genes, NLR family pyrin domain-containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3-deficient JEG-3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on HLA-C expression, thus implicating them in immune evasion at the maternal-fetal interface. We confirmed that NLRP2 suppresses HLA-C levels and described a unique role for NLRP7 in promoting HLA-C expression in JEG-3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine-tuned by ELF3 yet have acquired divergent functions to enable proper expression levels of HLA-C in EVT, presumably through modulating the degradation kinetics of IkBα. Targeting the ELF3-NLRP2/NLRP7-HLA-C axis may hold therapeutic potential for managing pregnancy-related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

To survive in the host, pathogenic bacteria need to be able to react to the unfavorable conditions that they encounter, like low pH, elevated temperatures, antimicrobial peptides and many more. These conditions may lead to unfolding of envelope proteins and this may be lethal. One of the mechanisms through which bacteria are able to survive these conditions is through the protease/foldase activity of the high temperature requirement A (HtrA) protein. The gut pathogen Clostridioides difficile encodes one HtrA homolog that is predicted to contain a membrane anchor and a single PDZ domain. The function of HtrA in C. difficile is hitherto unknown but previous work has shown that an insertional mutant of htrA displayed elevated toxin levels, less sporulation and decreased binding to target cells. Here, we show that HtrA is membrane associated and localized on the surface of C. difficile and characterize the requirements for proteolytic activity of recombinant soluble HtrA. In addition, we show that the level of HtrA in the bacteria heavily depends on its proteolytic activity. Finally, we show that proteolytic activity of HtrA is required for survival under acidic conditions. [ABSTRACT FROM AUTHOR]

The importance of fungi in ecological systems and pathogenicity hinges on their ability to search for nutrients, substrates, and hosts. Despite this, the question of whether fungal hyphae exhibit chemotropism toward them remains largely unresolved and requires close examination at the cellular level. Here, we designed a microfluidic device to assess hyphal chemotropism of Aspergillus nidulans in response to carbon and nitrogen sources, as well as pH. Within this device, hyphae could determine their growth direction in a two-layer flow with distinct compositions that were adjacent but non-mixing. Under conditions with and without a carbon source, hyphae changed growth direction to remain in the presence of a carbon source, but it was still difficult to distinguish between differences in growth and chemotropism. Although nitrogen sources such as ammonia and nitrate are important for growth, the hyphae indicated negative chemotropism to avoid them depending on the specific transporters. This fungus grows equally well at the colony level in the pH range of 4 to 9, but the hyphae exhibited chemotropism to acidic pH. The proton pump PmaA is vital for the chemotropism to acid pH, while the master regulatory for pH adaptation PacC is not involved, suggesting that chemotropism and adaptive growth via gene expression regulation are distinct regulatory mechanisms. Despite various plasma membrane transporters are distributed across membranes except at the hyphal tip, the control of growth direction occurs at the tip. Finally, we explored the mechanisms linking these two phenomena, tip growth and chemotropism. Fungi depend on their nutrient-seeking behavior for survival, yet how they find nutrients is not well understood. Using a microfluidic device, this study shows that hyphae of the fungus Aspergillus nidulans exhibit chemotropism towards nutrients, adjusting growth direction towards carbon sources and away from certain nitrogen sources and acidic pH. [ABSTRACT FROM AUTHOR]

Pioneer transcription factors, by virtue of their ability to target nucleosomal DNA in silent chromatin, play crucial roles in eliciting cell fate decisions during development and cellular reprogramming. In addition to their well‐established role in chromatin opening to activate gene expression programs, recent studies have demonstrated that pioneer factors have the complementary function of being able to silence the starting cell identity through targeted chromatin repression. Given recent discoveries regarding the repressive aspect of pioneer function, we discuss the basis by which pioneer factors can suppress alternative lineage programs in the context of cell fate control. [ABSTRACT FROM AUTHOR]

Background: Daphnia galeata is a suitable model organism for investigating predator-induced defense. Genes and pathways exhibiting differential expression between fish kairomone-treated and untreated groups in D. galeata have been identified. However, understanding of the significance of alternative splicing, a crucial process of the regulation of gene expression in eukaryotes, to this mechanism remains limited. This study measured life-history traits and conducted short-read RNA sequencing and long-read isoform sequencing of two Korean D. galeata genotypes (KB1 and KE2) to uncover the genetic mechanism underlying their phenotypic plasticity under predation stress. Results: KB1 exhibited strategies to enhance fertility and decrease body length when exposed to fish kairomones, while KE2 deployed an adaptive strategy to increase body length. Full-length transcriptomes from KB1 and KE2 yielded 65,736 and 57,437 transcripts, respectively, of which 32 differentially expressed transcripts (DETs) were shared under predation stress across both genotypes. Prominent DETs common to both genotypes were related to energy metabolism and the immune system. Additionally, differential alternative splicing (DAS) events were detected in both genotypes in response to fish kairomones. DAS genes shared between both genotypes may indicate their significant role in the post-transcriptional stress response to fish predation. Calpain-3, involved in digestion and nutrient absorption, was identified as a DAS gene in both genotypes when exposed to fish kairomones. In addition, the gene encoding thymosin beta, which is related to growth, was found to be a statistically significant DAS only in KB1, while that encoding ultraspiracle protein, also associated with growth, was only identified in KE2. Moreover, transcripts encoding proteins such as EGF-like domain-containing protein, vitellogenin fused with superoxide dismutase, and others were identified overlapping between DAS events and DETs and potentially elucidating their association with the observed phenotypic variation in each genotype. Conclusions: Our findings highlight the crucial role of alternative splicing in modulating transcriptome landscape under predation stress in D. galeata, emphasizing the requirement for integrating gene expression and splicing analyses in evolutionary adaptation studies. [ABSTRACT FROM AUTHOR]

Background: Pigs serve as a crucial source of protein in the human diet and play a fundamental role in ensuring food security. However, infectious diseases caused by bacteria or viruses are a major threat to effective global pig farming, jeopardizing human health. Peripheral blood mononuclear cells (PBMCs) are a mixture of immune cells that play crucial roles in immunity and disease resistance in pigs. Previous studies on the gene expression regulation patterns of PBMCs have concentrated on a single immune stimulus or immune cell subpopulation, which has limited our comprehensive understanding of the mechanisms of the pig immune response. Results: Here, we integrated and re-analyzed RNA-seq data published online for porcine PBMC stimulated by lipopolysaccharide (LPS), polyinosinic acid (PolyI:C), and various unknown microorganisms (EM). The results revealed that gene expression and its functional characterization are highly specific to the pathogen, identifying 603, 254, and 882 pathogen-specific genes and 38 shared genes, respectively. Notably, LPS and PolyI:C stimulation directly triggered inflammatory and immune-response pathways, while exposure to mixed microbes (EM) enhanced metabolic processes. These pathogen-specific genes were enriched in immune trait-associated quantitative trait loci (QTL) and eGenes in porcine immune tissues and were implicated in specific cell types. Furthermore, we discussed the roles of eQTLs rs3473322705 and rs1109431654 in regulating pathogen- and cell-specific genes CD300A and CD93, using cellular experiments. Additionally, by integrating genome-wide association studies datasets from 33 complex traits and diseases in humans, we found that pathogen-specific genes were significantly enriched for immune traits and metabolic diseases. Conclusions: We systematically analyzed the gene expression profiles of the three stimulations and demonstrated pathogen-specific and cell-specific gene regulation across different stimulations in porcine PBMCs. These findings enhance our understanding of shared and distinct regulatory mechanisms of genetic variants in pig immune traits. [ABSTRACT FROM AUTHOR]

Alternative transcription start site (TSS) usage regulation has been identified as a major means of gene expression regulation in metazoans. However, in fungi, its impact remains elusive as its study has thus far been restricted to model yeasts. Here, we first re-analyzed TSS-seq data to define genuine TSS clusters in 2 species of pathogenic Cryptococcus. We identified 2 types of TSS clusters associated with specific DNA sequence motifs. Our analysis also revealed that alternative TSS usage regulation in response to environmental cues is widespread in Cryptococcus, altering gene expression and protein targeting. Importantly, we performed a forward genetic screen to identify a unique transcription factor (TF) named Tur1, which regulates alternative TSS (altTSS) usage genome-wide when cells switch from exponential phase to stationary phase. ChiP-Seq and DamID-Seq analyses suggest that at some loci, the role of Tur1 might be direct. Tur1 has been previously shown to be essential for virulence in C. neoformans. We demonstrated here that a tur1Δ mutant strain is more sensitive to superoxide stress and phagocytosed more efficiently by macrophages than the wild-type (WT) strain. Alternative transcription start site (altTSS) usage is one of the major means of gene regulation in animals but is unknown in non-yeast fungi. This study reveals widespread altTSS in Cryptococcus that alters gene expression and protein targeting, regulated by a single transcription factor, Tur1, in response to environmental cues. [ABSTRACT FROM AUTHOR]

sulfur-containing amino acids have been reported to patriciate in gene regulation, DNA methylation, protein synthesis and other physiological or pathological processes. In recent years, metabolism-related molecules of sulfur-containing amino acids affecting the occurrence, development and treatment of tumors have been implicated in various disorders, especially in leukemia. Here, we summarize current knowledge on the sulfur-containing amino acid metabolism pathway in leukemia and examine ongoing efforts to target this pathway, including treatment strategies targeting (a) sulfur-containing amino acids, (b) metabolites of sulfur-containing amino acids, and (c) enzymes and cofactors related to sulfur-containing amino acid metabolism in leukemia. Future leukemia therapy will likely involve innovative strategies targeting the sulfur-containing amino acid metabolism pathway. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are post‐transcriptional gene regulators. In the miRNA pathway's cytoplasmic part, the miRNA is processed from a hairpin‐structured precursor to a double‐stranded (ds) mature RNA and ultimately to a single‐stranded mature miRNA. In insects, ingesting these two ds forms can regulate the target gene expression; this inspired the trophic miRNA's use as a functional genomics and pest management tool. However, systematic studies enabling comparisons of pre‐ and mature forms, dosages, administration times and instar‐wise effects on target transcripts and phenotypes, which can help develop a miRNA administration method, are unavailable due to the different focuses of the previous investigations. We investigated the impact of trophically delivered Px‐let‐7 miRNA on the lepidopteran pest Plutella xylostella, to compare the efficacies of its pre‐ and ds‐mature forms. Continuous feeding on the miRNA‐supplemented diet suppressed expressions of FTZ‐F1 and E74, the target ecdysone pathway genes. Both the pre‐let‐7 and mature let‐7 miRNA forms similarly downregulated the target transcripts in all four larval instars. Pre‐let‐7 and let‐7 ingestions decreased larval mass and instar duration and increased mortality in all instars, exhibiting adverse effects on larval growth and development. miRNA processing Dicer‐1 and AGO‐1's upregulations upon miRNA ingestion denoted the systemic miRNA spread in larval tissues. The scrambled sequence controls did not affect the target transcripts, suggesting the sequence‐specific targeting by the mature miRNA and hairpin cassette's non‐involvement in the target downregulation. This work provides a framework for miRNA and target gene function analyses and potentiates the trophic miRNA's utility in pest management. [ABSTRACT FROM AUTHOR]

Background: Vitiligo is an auto-immune progressive depigmentation disorder of the skin due to loss of melanocytes. Genetic risk is one of the important factors for development of vitiligo. Preponderance of vitiligo in certain ethnicities is known which can be analysed by understanding the distribution of allele frequencies across normal populations. Earlier GWAS identified 108 risk alleles for vitiligo in Europeans and East Asians. In this study, 64 of these risk alleles were used for analysing their enrichment and depletion across populations (1000 Genomes Project and IndiGen) with reference to 1000 Genomes dataset. Genetic risk scores were calculated and Fisher's exact test was performed to understand statistical significance of their variation in each population with respect to 1000 Genomes dataset as reference. In addition to SNPs reported in GWAS, significant variation in allele frequencies of 1079 vitiligo-related genes were also analysed. Two-tailed Chi-square test and Bonferroni's multiple adjustment values along with fixation index (≥ 0.5) and minimum allele frequency (≥ 0.05) were calculated and used to prioritise the variants based on pairwise comparison across populations. Results: Risk alleles rs1043101 and rs10768122 belong to 3 prime UTR of glutamate receptor gene SLC1A2 are found to be highly enriched in the South Asian population when compared with the 'global normal' population. Intron variant rs4766578 (ATXN2) was found to be deleted in SAS, EAS and AFR and enriched in EUR and AMR1. This risk allele is found to be under positive selection in SAS, AMR1 and EUR. From the ancillary vitiligo gene list, nonsynonymous variant rs16891982 was found to be enriched in the European and the Admixed American populations and depleted in all others. rs2279238 and rs11039155 belonging to the LXR-α gene involved in regulation of metalloproteinase 2 and 9 (melanocyte precursors) were found to be associated with vitiligo in the North Indian population (in earlier study). Conclusion: The differential enrichment/depletion profile of the risk alleles provides insight into the underlying inter-population variations. This would provide clues towards prioritisation of SNPs associated with vitiligo thereby elucidating its preponderance in different ethnic groups. [ABSTRACT FROM AUTHOR]

In eukaryotes, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are reversibly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increasing evidence highlights histone acetylation plays essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance of histone acetylation in the regulation of abiotic stress responses including temperature, light, salt and drought stress. This information will contribute to our understanding of how plants adapt to environmental changes. As the mechanisms of epigenetic regulation are conserved in many plants, research in this field has potential applications in improvement of agricultural productivity. [ABSTRACT FROM AUTHOR]

Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) ranks as the third most prevalent malignancy globally, with a concerning rise in incidence among young adults. Despite progress in understanding genetic predispositions and lifestyle risk factors, the intricate molecular mechanisms of CRC demand exploration. MicroRNAs (miRNAs) emerge as key regulators of gene expression and their deregulation in tumor cells play pivotal roles in cancer progression. Methods: NanoString's nCounter technology was utilized tomeasure the expression of 827 cancer-related miRNAs in tumor tissue and adjacent non-involved normal colon tissue from five patients with locoregional CRC progression. These expression profiles were then compared to those from the primary colon adenocarcinoma (COAD) cohort in The Cancer Genome Atlas (TCGA). Results and discussion: Intriguingly, 156 miRNAs showed a contrasting dysregulation pattern in reccurent tumor compared to their expression in the TCGA COAD cohort. This observation implies dynamic alterations in miRNA expression patterns throughout disease progression. Our exploratory study contributes to understanding the regulatory landscape of recurrent CRC, emphasizing the role of miRNAs in disease relapse. Notable findings include the prominence of let-7 miRNA family, dysregulation of key target genes, and dynamic changes in miRNA expression patterns during progression. Univariate Cox proportional hazard models highlighted miRNAs associated with adverse outcomes and potential protective factors. The study underscores the need for more extensive investigations into miRNA dynamics during tumor progression and the value of stage specific biomarkers for prognosis. [ABSTRACT FROM AUTHOR]

Background: Trichothiodystrophy-1 (TTD1) is an autosomal-recessive disease and caused by mutations in ERCC2, a gene coding for a subunit of the TFIIH transcription and nucleotide-excision repair (NER) factor. In almost half of these patients infectious susceptibility has been reported but the underlying molecular mechanism leading to immunodeficiency is largely unknown. Objective: The aim of this study was to perform extended molecular and immunological phenotyping in patients suffering from TTD1. Methods: Cellular immune phenotype was investigated using multicolor flow cytometry. DNA repair efficiency was evaluated in UV-irradiation assays. Furthermore, early BCR activation events and proliferation of TTD1 lymphocytes following DNA damage induction was tested. In addition, we performed differential gene expression analysis in peripheral lymphocytes of TTD1 patients. Results: We investigated three unrelated TTD1 patients who presented with recurrent infections early in life of whom two harbored novel ERCC2 mutations and the third patient is a carrier of previously described pathogenic ERCC2 mutations. Hypogammaglobulinemia and decreased antibody responses following vaccination were found. TTD1 B-cells showed accumulation of g-H2AX levels, decreased proliferation activity and reduced cell viability following UV irradiation. mRNA sequencing analysis revealed significantly downregulated genes needed for B-cell development and activation. Analysis of B-cell subpopulations showed low numbers of naïve and transitional B-cells in TTD1 patients, indicating abnormal B-cell differentiation in vivo. Conclusion: In summary, our analyses confirmed the pathogenicity of novel ERCC2 mutations and show that ERCC2 deficiency is associated with antibody deficiency most likely due to altered B-cell differentiation resulting from impaired BCR-mediated B-cell activation and activation-induced gene transcription. [ABSTRACT FROM AUTHOR]

Chromosome rearrangements may distort 3D chromatin architectures and thus change gene regulation, yet how 3D chromatin structures evolve in insects is largely unknown. Here, we obtain chromosome-level genomes for four butterfly species, Graphium cloanthus, Graphium sarpedon, Graphium eurypylus with 2n = 30, 40, and 60, respectively, and Papilio bianor with 2n = 60. Together with large-scale Hi-C data, we find that inter-chromosome rearrangements very rarely disrupted the pre-existing 3D chromatin structure of ancestral chromosomes. However, some intra-chromosome rearrangements changed 3D chromatin structures compared to the ancestral configuration. We find that new TADs and subTADs have emerged across the rearrangement sites where their adjacent compartments exhibit uniform types. Two intra-chromosome rearrangements altered Rel and lft regulation, potentially contributing to wing patterning differentiation and host plant choice. Notably, butterflies exhibited chromatin loops between Hox gene cluster ANT-C and BX-C, unlike Drosophila. Our CRISPR-Cas9 experiments in butterflies confirm that knocking out the CTCF binding site of the loops in BX-C affected the phenotypes regulated by Antp in ANT-C, resulting in legless larva. Our results reveal evolutionary patterns of insect 3D chromatin structures and provide evidence that 3D chromatin structure changes can play important roles in the evolution of traits. There are extensive genome rearrangements among butterflies which may distort 3D chromatin structures. Here, the authors use multi-omics techniques in Graphium butterflies to reveal evolutionary patterns of insect 3D chromatin structures and its significant role in trait evolution. [ABSTRACT FROM AUTHOR]

Summary: Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies. The PCA pathway, essential for synthesizing CoA and AcCoA from vitamin B5, plays a crucial role in fungal cellular processes. Targeting this pathway could enhance antifungal drug efficacy by affecting vacuolar morphology and drug detoxification. [ABSTRACT FROM AUTHOR]

Photochemical internalization is an efficient strategy relying on photodynamic reactions to promote siRNA endosomal escape for the success of RNA‐interference gene regulation, which makes gene‐photodynamic combined therapy highly synergistic and efficient. However, it is still desired to explore capable carriers to improve the delivery efficiency of the immiscible siRNA and organic photosensitizers simultaneously. Herein, we employ a micellar nanostructure (PSNA) self‐assembled from polymer‐DNA molecular chimeras to fulfill this task. PSNA can plentifully load photosensitizers in its hydrophobic core simply by the nanoprecipitation method. Moreover, it can organize siRNA self‐assembly by the densely packed DNA shell, which leads to a higher loading capacity than the typical electrostatic condensation method. The experimental results prove that this PSNA carrier can greatly facilitate siRNA escape from the endosome/lysosome and enhance transfection. Accordingly, the PSNA‐administrated therapy exhibits a significantly improved anti‐tumor efficacy owing to the highly efficient co‐delivery capability. [ABSTRACT FROM AUTHOR]

Our previous research found that fecal microbiota transplantation (FMT) and inulin synergistically affected the intestinal barrier and immune system function in chicks. However, does it promote the early immunity of the poultry gut-associated lymphoid tissue (GALT)? How does it regulate the immunity? We evaluated immune-related indicators in the serum, cecal tonsil, and intestine to determine whether FMT synergistic inulin had a stronger impact on gut health and which gene expression regulation was affected. The results showed that FMT synergistic inulin increased TGF-β secretion and intestinal goblet cell number and MUC2 expression on day 14. Expression of BAFFR, PAX5, CXCL12, and IL-2 on day 7 and expression of CXCR4 and IL-2 on day 14 in the cecal tonsils significantly increased. The transcriptome indicated that CD28 and CTLA4 were important regulatory factors in intestinal immunity. Correlation analysis showed that differential genes were related to the immunity and development of the gut and cecal tonsil. FMT synergistic inulin promoted the development of GALT, which improved the early-stage immunity of the intestine by regulating CD28 and CTLA4. This provided new measures for replacing antibiotic use and reducing the use of therapeutic drugs while laying a technical foundation for achieving anti-antibiotic production of poultry products. [ABSTRACT FROM AUTHOR]

Background: Phosphorus (P) deficiency, a major nutrient stress, greatly hinders plant growth. Phosphate (Pi) uptake in plant roots relies on PHT1 family transporters. However, melon (Cucumis melo L.) lacks comprehensive identification and characterization of PHT1 genes, particularly their response patterns under diverse stresses. Results: This study identified and analyzed seven putative CmPHT1 genes on chromosomes 3, 4, 5, 6, and 7 using the melon genome. Phylogenetic analysis revealed shared motifs, domain compositions, and evolutionary relationships among genes with close histories. Exon number varied from 1 to 3. Collinearity analysis suggested segmental and tandem duplications as the primary mechanisms for CmPHT1 gene family expansion. CmPHT1;4 and CmPHT1;5 emerged as a tandemly duplicated pair. Analysis of cis-elements in CmPHT1 promoters identified 14 functional categories, including putative PHR1-binding sites (P1BS) in CmPHT1;4, CmPHT1;6, and CmPHT1;7. We identified that three WRKY transcription factors regulated CmPHT1;5 expression by binding to its W-box element. Notably, CmPHT1 promoters harbored cis-elements responsive to hormones and abiotic factors. Different stresses regulated CmPHT1 expression differently, suggesting that the adjusted expression patterns might contribute to plant adaptation. Conclusions: This study unveils the characteristics, evolutionary diversity, and stress responsiveness of CmPHT1 genes in melon. These findings lay the foundation for in-depth investigations into their functional mechanisms in Cucurbitaceae crops. [ABSTRACT FROM AUTHOR]

In metazoans, microRNAs (miRNAs) are essential regulators of gene expression, affecting critical cellular processes from differentiation and proliferation, to homeostasis. During miRNA biogenesis, the miRNA strand that loads onto the RNA-induced Silencing Complex (RISC) can vary, leading to changes in gene targeting and modulation of biological pathways. To investigate the impact of these "arm switching" events on gene regulation, we analyzed a diverse range of tissues and developmental stages in zebrafish by comparing 5p and 3p arms accumulation dynamics between embryonic developmental stages, adult tissues, and sexes. We also compared variable arm usage patterns observed in zebrafish to other vertebrates including arm switching data from fish, birds, and mammals. Our comprehensive analysis revealed that variable arm usage events predominantly take place during embryonic development. It is also noteworthy that isomiR occurrence correlates to changes in arm selection evidencing an important role of microRNA distinct isoforms in reinforcing and modifying gene regulation by promoting dynamics switches on miRNA 5p and 3p arms accumulation. Our results shed new light on the emergence and coordination of gene expression regulation and pave the way for future investigations in this field. [ABSTRACT FROM AUTHOR]

Despite the array of mammalian transgene switches available for regulating therapeutic protein expression in response to small molecules or physical stimuli, issues remain, including cytotoxicity of chemical inducers and limited biocompatibility of physical cues. This study introduces gene switches driven by short peptides comprising eight or fewer amino acid residues. Utilizing a competence regulator (ComR) and sigma factor X‐inducing peptide (XIP) from Streptococcus vestibularis as the receptor and inducer, respectively, this study develops two strategies for a peptide‐activated transgene control system. The first strategy involves fusing ComR with a transactivation domain and utilizes ComR‐dependent synthetic promoters to drive expression of the gene‐of‐interest, activated by XIP, thereby confirming its membrane penetrability and intracellular functionality. The second strategy features an orthogonal synthetic receptor exposing ComR extracellularly (ComREXTRA), greatly increasing sensitivity with exceptional responsiveness to short peptides. In a proof‐of‐concept study, peptides are administered to type‐1 diabetic mice with microencapsulated engineered human cells expressing ComREXTRA for control of insulin expression, restoring normoglycemia. It is envisioned that this system will encourage the development of short peptide drugs and promote the introduction of non‐toxic, orthogonal, and highly biocompatible personalized biopharmaceuticals for gene‐ and cell‐based therapies. [ABSTRACT FROM AUTHOR]

The role of processing bodies (P-bodies) in tumorigenesis and tumor progression is not well understood. Here, we showed that the oncogenes YAP/TAZ promote P-body formation in a series of cancer cell lines. Mechanistically, both transcriptional activation of the P-body-related genes SAMD4A, AJUBA, and WTIP and transcriptional suppression of the tumor suppressor gene PNRC1 are involved in enhancing the effects of YAP/TAZ on P-body formation in colorectal cancer (CRC) cells. By reexpression of PNRC1 or knockdown of P-body core genes (DDX6, DCP1A, and LSM14A), we determined that disruption of P-bodies attenuates cell proliferation, cell migration, and tumor growth induced by overexpression of YAP5SA in CRC. Analysis of a pancancer CRISPR screen database (DepMap) revealed co-dependencies between YAP/TEAD and the P-body core genes and correlations between the mRNA levels of SAMD4A, AJUBA, WTIP, PNRC1, and YAP target genes. Our study suggests that the P-body is a new downstream effector of YAP/TAZ, which implies that reexpression of PNRC1 or disruption of P-bodies is a potential therapeutic strategy for tumors with active YAP. [ABSTRACT FROM AUTHOR]

Summary N6‐methyladenosine (m6A) RNA modification is the most prevalent messenger RNA (mRNA) modification in eukaryotes and plays critical roles in the regulation of gene expression. m6A is a reversible RNA modification that is deposited by methyltransferases (writers) and removed by demethylases (erasers). The function of m6A erasers in plants is highly diversified and their roles in cereal crops, especially in reproductive development essential for crop yield, are largely unknown. Here, we demonstrate that rice OsALKBH5 acts as an m6A demethylase required for the normal progression of male meiosis. OsALKBH5 is a nucleo‐cytoplasmic protein, highly enriched in rice anthers during meiosis, that associates with P‐bodies and exon junction complexes, suggesting that it is involved in regulating mRNA processing and abundance. Mutations of OsALKBH5 cause reduced double‐strand break (DSB) formation, severe defects in DSB repair, and delayed meiotic progression, leading to complete male sterility. Transcriptome analysis and m6A profiling indicate that OsALKBH5‐mediated m6A demethylation stabilizes the mRNA level of multiple meiotic genes directly or indirectly, including several genes that regulate DSB formation and repair. Our study reveals the indispensable role of m6A metabolism in post‐transcriptional regulation of meiotic progression in rice. [ABSTRACT FROM AUTHOR]

Light serves as a crucial external zeitgeber for maintaining and restoring physiological homeostasis in most organisms. Disrupting of light rhythms often leads to abnormal immune function, characterized by excessive inflammatory responses. However, the underlying regulatory mechanisms behind this phenomenon remain unclear. To address this concern, we use in vivo imaging to establish inflammation models in zebrafish, allowing us to investigate the effects and underlying mechanisms of light disruption on neutrophil recruitment. Our findings reveal that under sustained light conditions (LL), neutrophil recruitment in response to caudal fin injury and otic vesicle inflammation is significantly increased. This is accompanied by elevated levels of histone (H3K18) lactylation and reactive oxygen species (ROS) content. Through ChIP-sequencing and ChIP‒qPCR analysis, we discover that H3K18 lactylation regulates the transcriptional activation of the duox gene, leading to ROS production. In turn, ROS further promote H3K18 lactylation, forming a positive feedback loop. This loop, driven by H3K18 lactylation-ROS, ultimately results in the over recruitment of neutrophils to inflammatory sites in LL conditions. Collectively, our study provides evidence of a mutual loop between histone lactylation and ROS, exacerbating neutrophil recruitment in light disorder conditions, emphasizing the significance of maintaining a proper light-dark cycle to optimize immune function. Through ChIP-sequencing and ChIP‒qPCR analysis, authors discover a positive feedback loop between histone lactylation and reactive oxygen species which exacerbates neutrophil recruitment under light disorder conditions in Zebrafish. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) intricately navigate the vast genomic landscape to locate and bind specific DNA sequences for the regulation of gene expression programs. These interactions occur within a dynamic cellular environment, where both DNA and TF proteins experience continual chemical and structural perturbations, including epigenetic modifications, DNA damage, mechanical stress, and post-translational modifications (PTMs). While many of these factors impact TF-DNA binding interactions, understanding their effects remains challenging and incomplete. This review explores the existing literature on these dynamic changes and their potential impact on TF-DNA interactions. [ABSTRACT FROM AUTHOR]

Introduction: Status epilepticus (SE) is a seizure lasting more than 5 min that can have lethal consequences or lead to various neurological disorders, including epilepsy. Using a pilocarpine-induced SE model in mice we investigated temporal changes in the hippocampal transcriptome. Methods: We performed mRNA-seq and microRNA-seq analyses at various times after drug treatment. Results: At 1 h after the start of seizures, hippocampal cells upregulated transcription of immediate early genes and genes involved in the IGF-1, ERK/MAPK and RNAPolII/transcription pathways. At 8 h, we observed changes in the expression of genes associated with oxidative stress, overall transcription downregulation, particularly for genes related to mitochondrial structure and function, initiation of a stress response through regulation of ribosome and translation/EIF2 signaling, and upregulation of an inflammatory response. During the middle of the latent period, 36 h, we identified upregulation of membrane components, cholesterol synthesis enzymes, channels, and extracellular matrix (ECM), as well as an increased inflammatory response. At the end of the latent period, 120 h, most changes in expression were in genes involved in ion transport, membrane channels, and synapses. Notably, we also elucidated the involvement of novel pathways, such as cholesterol biosynthesis pathways, iron/BMP/ferroptosis pathways, and circadian rhythms signaling in SE and epileptogenesis. Discussion: These temporal changes in metabolic reactions indicate an immediate response to injury followed by recovery and regeneration. CREB was identified as the main upstream regulator. Overall, our data provide new insights into molecular functions and cellular processes involved at different stages of seizures and offer potential avenues for effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of non-coding RNAs (ncRNAs) that can participate in biological processes such as gene expression, growth, and development. However, little has been explored about the function of circRNAs in the development of Apis cerana larval guts. By using our previously gained deep sequencing data from the guts of A. cerana worker larvae at 4-, 5-, and 6-day-old (Ac4, Ac5, and Ac6 groups), the expression pattern and regulatory role of circular RNAs (circRNAs) during the development process was comprehensively investigated, with a focus on differentially expressed circRNAs (DEcircRNAs) relevant to immunity pathways and developmental signaling pathways, followed by validation of the binding relationships among a key competing endogenous RNA (ceRNA) axis. Here, 224 (158) DEcircRNAs were detected in the Ac4 vs. Ac5 (Ac5 vs. Ac6) comparison group. It's suggested that 172 (123) parental genes of DEcircRNAs were involved in 26 (20) GO terms such as developmental process and metabolic process and 138 (136) KEGG pathways like Hippo and Wnt signaling pathways. Additionally, ceRNA network analysis indicated that 21 (11) DEcircRNAs could target seven (three) DEmiRNAs, further targeting 324 (198) DEmRNAs. These DEmRNAs can be annotated to 33 (26) GO terms and 168 (200) KEGG pathways, including 12 (16) cellular and humoral immune pathways (endocytosis, lysosome, Jak-STAT, etc.) and 10 (nine) developmental signaling pathways (Hippo, mTOR, Hedgehog, etc.). Interestingly, DEcircRNAs in these two comparison groups could target the same ace-miR-6001-y, forming complex subnetworks. The results of PCR and Sanger sequencing confirmed the back- splicing sites within four randomly selected DEcircRNAs. RT-qPCR detection of these four DEcircRNAs verified the reliability of the used transcriptome data. The results of dual-luciferase reporter assay verified the binding relationships between novel_circ_001627 and ace-miR-6001-y and between ace-miR-6001-y and apterous-like. Our data demonstrated that DEcircRNAs were likely to modulate the developmental process of the A. cerana worker larval guts via regulation of parental gene transcription and ceRNA network, and novel_circ_001627/ace-miR-6001-y/apterous-like was a potential regulatory axis in the larval gut development. Findings from this work offer a basis and a candidate ceRNA axis for illustrating the circRNA-modulated mechanisms underlying the A. cerana larval guts. [ABSTRACT FROM AUTHOR]

Background: The progress of the cell cycle of yeast involves the regulatory relationships between genes and the interactions proteins. However, it is still obscure which type of protein plays a decisive role in regulation and how to identify the vital nodes in the regulatory network. To elucidate the sensitive node or gene in the progression of yeast, here, we select 8 crucial regulatory factors from the yeast cell cycle to decipher a specific network and propose a simple mixed K2 algorithm to identify effectively the sensitive nodes and genes in the evolution of yeast. Results: Considering the multivariate of cell cycle data, we first utilize the K2 algorithm limited to the stationary interval for the time series segmentation to measure the scores for refining the specific network. After that, we employ the network entropy to effectively screen the obtained specific network, and simulate the gene expression data by a normal distribution approximation and the screened specific network by the partial least squares method. We can conclude that the robustness of the specific network screened by network entropy is better than that of the specific network with the determined relationship by comparing the obtained specific network with the determined relationship. Finally, we can determine that the node CDH1 has the highest score in the specific network through a sensitivity score calculated by network entropy implying the gene CDH1 is the most sensitive regulatory factor. Conclusions: It is clearly of great potential value to reconstruct and visualize gene regulatory networks according to gene databases for life activities. Here, we present an available algorithm to achieve the network reconstruction by measuring the network entropy and identifying the vital nodes in the specific nodes. The results indicate that inhibiting or enhancing the expression of CDH1 can maximize the inhibition or enhancement of the yeast cell cycle. Although our algorithm is simple, it is also the first step in deciphering the profound mystery of gene regulation. [ABSTRACT FROM AUTHOR]

Background: Boron (B) is an essential micronutrient for plants. Inappropriate B supply detrimentally affects the productivity of numerous crops. Understanding of the molecular responses of plants to different B supply levels would be of significance in crop improvement and cultivation practices to deal with the problem. Results: We conducted a comprehensive analysis of the transcriptome and proteome of tobacco seedlings to investigate the expression changes of genes/proteins in response to different B supply levels, with a particular focus on B deficiency. The global gene and protein expression profiles revealed the potential mechanisms involved in the responses of tobacco to B deficiency, including up-regulation of the NIP5;1-BORs module, complex regulation of genes/proteins related to cell wall metabolism, and up-regulation of the antioxidant machinery. Conclusion: Our results demonstrated that B deficiency caused severe morphological and physiological disorders in tobacco seedlings, and revealed dynamic expression changes of tobacco genes/proteins in response to different B supply levels, especially to B deficiency, thus offering valuable insights into the molecular responses of tobacco to B deficiency. [ABSTRACT FROM AUTHOR]

Biological signal transduction networks are central to information processing and regulation of gene expression across all domains of life. Dysregulation is known to cause a wide array of diseases, including cancers. Here I introduce self-consistent signal transduction analysis, which utilizes genome-scale -omics data (specifically transcriptomics and/or proteomics) in order to predict the flow of information through these networks in an individualized manner. I apply the method to the study of endocrine therapy in breast cancer patients, and show that drugs that inhibit estrogen receptor α elicit a wide array of antitumoral effects, and that their most clinically-impactful ones are through the modulation of proliferative signals that control the genes GREB1, HK1, AKT1, MAPK1, AKT2, and NQO1. This method offers researchers a valuable tool in understanding how and why dysregulation occurs, and how perturbations to the network (such as targeted therapies) effect the network itself, and ultimately patient outcomes. [ABSTRACT FROM AUTHOR]

Summary The Arabidopsis BLADE‐ON‐PETIOLE (BOP) genes are primarily known for their roles in regulating leaf and floral patterning. However, the broader functions of BOPs in regulating plant traits remain largely unexplored. In this study, we investigated the role of the Gossypium hirsutum BOP1 gene in the regulation of fibre length and plant height through the brassinosteroid (BR) signalling pathway. Transgenic cotton plants overexpressing GhBOP1 display shorter fibre lengths and reduced plant height compared to the wild type. Conversely, GhBOP1 knockdown led to increased plant height and longer fibre, indicating a connection with phenotypes influenced by the BR pathway. Our genetic evidence supports the notion that GhBOP1 regulates fibre length and plant height in a GhBES1‐dependent manner, with GhBES1 being a major transcription factor in the BR signalling pathway. Yeast two‐hybrid, luciferase complementation assay and pull‐down assay results demonstrated a direct interaction between GhBOP1 and GhSUMO1, potentially forming protein complexes with GhBES1. In vitro and in vivo SUMOylation analyses revealed that GhBOP1 functions in an E3 ligase‐like manner to mediate GhBES1 SUMOylation and subsequent degradation. Therefore, our study not only uncovers a novel mechanism of GhBES1 SUMOylation but also provides significant insights into how GhBOP1 regulates fibre length and plant height by controlling GhBES1 accumulation. [ABSTRACT FROM AUTHOR]