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Periodontitis is a chronic inflammatory disease caused by plaque biofilm, and the homeostasis of the periodontal microenvironment is crucial for periodontal health. The epigenetics explores how the environmental and other non-genetic factors regulate the gene expression without changing the DNA nucleotide sequence, thereby affecting the occurrence and development of this disease. The histone acetylation modification is one of the common epigenetic modifications, primarily regulated by the histone acetyltransferases and histone deacetylases. Imbalance in this regulation can lead to the gene regulatory disorders, causing the chronic inflammation, autoimmune diseases and cancer. Recent studies have shown there is a clear correlation between histone acetylation modifications and the development of periodontitis. This paper discusses the changes in histone acetylation modifications in the gingival epithelial cells, immune cells, and periodontal ligament stem cells during periodontitis, elucidating the role and molecular mechanisms of histone acetylation modifications in the development of periodontitis and providing the basis for the epigenetic treatment of periodontitis. [ABSTRACT FROM AUTHOR]

Models intended to describe the time evolution of a gene network must somehow include transcription, the DNA-templated synthesis of RNA, and translation, the RNA-templated synthesis of proteins. In eukaryotes, the DNA template for transcription can be very long, often consisting of tens of thousands of nucleotides, and lengthy pauses may punctuate this process. Accordingly, transcription can last for many minutes, in some cases hours. There is a long history of introducing delays in gene expression models to take the transcription and translation times into account. Here we study a family of detailed transcription models that includes initiation, elongation, and termination reactions. We establish a framework for computing the distribution of transcription times, and work out these distributions for some typical cases. For elongation, a fixed delay is a good model provided elongation is fast compared to initiation and termination, and there are no sites where long pauses occur. The initiation and termination phases of the model then generate a nontrivial delay distribution, and elongation shifts this distribution by an amount corresponding to the elongation delay. When initiation and termination are relatively fast, the distribution of elongation times can be approximated by a Gaussian. A convolution of this Gaussian with the initiation and termination time distributions gives another analytic approximation to the transcription time distribution. If there are long pauses during elongation, because of the modularity of the family of models considered, the elongation phase can be partitioned into reactions generating a simple delay (elongation through regions where there are no long pauses), and reactions whose distribution of waiting times must be considered explicitly (initiation, termination, and motion through regions where long pauses are likely). In these cases, the distribution of transcription times again involves a nontrivial part and a shift due to fast elongation processes.

Objective R-loops are DNA:RNA triplex hybrids, and their metabolism is tightly regulated by transcriptional regulation, DNA damage response, and chromatin structure dynamics. R-loop homeostasis is dynamically regulated and closely associated with gene transcription in mouse zygotes. However, the factors responsible for regulating these dynamic changes in the R-loops of fertilized mouse eggs have not yet been investigated. This study examined the functions of candidate factors that interact with R-loops during zygotic gene activation. Methods In this study, we used publicly available next-generation sequencing datasets, including low-input ribosome profiling analysis and polymerase II chromatin immunoprecipitation-sequencing (ChIP-seq), to identify potential regulators of R-loop dynamics in zygotes. These datasets were downloaded, reanalyzed, and compared with mass spectrometry data to identify candidate factors involved in regulating R-loop dynamics. To validate the functions of these candidate factors, we treated mouse zygotes with chemical inhibitors using in vitro fertilization. Immunofluorescence with an anti-R-loop antibody was then performed to quantify changes in R-loop metabolism. Results We identified DEAD-box-5 (DDX5) and histone deacetylase-2 (HDAC2) as candidates that potentially regulate R-loop metabolism in oocytes, zygotes and two-cell embryos based on change of their gene translation. Our analysis revealed that the DDX5 inhibition of activity led to decreased R-loop accumulation in pronuclei, indicating its involvement in regulating R-loop dynamics. However, the inhibition of histone deacetylase-2 activity did not significantly affect R-loop levels in pronuclei. Conclusion These findings suggest that dynamic changes in R-loops during mouse zygote development are likely regulated by RNA helicases, particularly DDX5, in conjunction with transcriptional processes. Our study provides compelling evidence for the involvement of these factors in regulating R-loop dynamics during early embryonic development.

Epigenetic regulation, which is characterized by reversible and heritable genetic alterations without changing DNA sequences, has recently been increasingly studied in diseases. Histone variant regulation is an essential component of epigenetic regulation. The substitution of canonical histones by histone variants profoundly alters the local chromatin structure and modulates DNA accessibility to regulatory factors, thereby exerting a pivotal influence on gene regulation and DNA damage repair. Histone H2A variants, mainly including H2A.Z, H2A.B, macroH2A, and H2A.X, are the most abundant identified variants among all histone variants with the greatest sequence diversity. Harboring varied chromatin occupancy and structures, histone H2A variants perform distinct functions in gene transcription and DNA damage repair. They are implicated in multiple pathophysiological mechanisms and the emergence of different illnesses. Cancer, embryonic development abnormalities, neurological diseases, metabolic diseases, and heart diseases have all been linked to histone H2A variant alterations. This review focuses on the functions of H2A histone variants in mammals, including H2A.Z, H2A.B, macroH2A, and H2A.X, and their current roles in various diseases. [ABSTRACT FROM AUTHOR]

Lactate, a metabolic byproduct, has gained recognition as a highly influential signaling molecule. Lactylation, an emerging form of post-translational modification derived from lactate, plays a crucial role in numerous cellular processes such as inflammation, embryonic development, tumor proliferation, and metabolism. However, the precise molecular mechanisms through which lactylation governs these biological functions in both physiological and pathological contexts remain elusive. Hence, it is imperative to provide a comprehensive overview of lactylation in order to elucidate its significance in biological processes and establish a foundation for forthcoming investigations. This review aims to succinctly outline the process of lactylation modification and the characterization of protein lactylation across diverse organisms. Additionally, A summary of the regulatory mechanisms of lactylation in cellular processes and specific diseases is presented. Finally, this review concludes by delineating existing research gaps in lactylation and proposing primary directions for future investigations. [ABSTRACT FROM AUTHOR]

The intricate landscape of cellular processes governing gene transcription, chromatin organization, and genome stability is a fascinating field of study. A key player in maintaining this delicate equilibrium is the cohesin complex, a molecular machine with multifaceted roles. This review presents an in‐depth exploration of these intricate connections and their significant impact on various human diseases. [ABSTRACT FROM AUTHOR]

Viruses exploit the host cell machinery to enable infection and propagation. This review discusses the complex landscape of DNA virus–host interactions, focusing primarily on herpesviruses and adenoviruses, which replicate in the nucleus of infected cells, and vaccinia virus, which replicates in the cytoplasm. We discuss experimental approaches used to discover and validate interactions of host proteins with viral genomes and how these interactions impact processes that occur during infection, including the host DNA damage response and viral genome replication, repair, and transcription. We highlight the current state of knowledge regarding virus–host protein interactions and also outline emerging areas and future directions for research. [ABSTRACT FROM AUTHOR]

Metabolism includes anabolism and catabolism, which play an essential role in many biological processes. Chromatin modifications are post‐translational modifications of histones and nucleic acids that play important roles in regulating chromatin‐associated processes such as gene transcription. There is a tight connection between metabolism and chromatin modifications. Many metabolic enzymes and metabolites coordinate cellular activities with alterations in nutrient availability by regulating gene expression through epigenetic mechanisms such as DNA methylation and histone modifications. The dysregulation of gene expression by metabolism and epigenetic modifications may lead to diseases such as diabetes and cancer. Recent studies reveal that metabolic enzymes and metabolites specifically regulate chromatin modifications, including modification types, modification residues and chromatin regions. This specific regulation has been implicated in the development of human diseases, yet the underlying mechanisms are only beginning to be uncovered. In this review, we summarise recent studies of the molecular mechanisms underlying the metabolic regulation of histone and DNA modifications and discuss how they contribute to pathogenesis. We also describe recent developments in technologies used to address the key questions in this field. We hope this will inspire further in‐depth investigations of the specific regulatory mechanisms involved, and most importantly will shed lights on the development of more effective disease therapies. [ABSTRACT FROM AUTHOR]

Gap junctional connection (GJC) in the cumulus–oocyte complex (COC) provides necessary support for message communication and nutrient transmission required for mammalian oocyte maturation. Cyclic adenosine monophosphate (cAMP) is not only a prerequisite for regulating oocyte meiosis, but also the key intercellular factor for affecting GJC function in COCs. However, there are no reports on whether cAMP regulates connexin 37 (Cx37) expression, one of the main connexin proteins, in sheep COCs. In this study, the expression of Cx37 protein and gene in immature sheep COC was detected using immunohistochemistry and PCR. Subsequently, the effect of cAMP on Cx37 expression in sheep COCs cultured in a gonadotropin-free culture system for 10 min or 60 min was evaluated using competitive ELISA, real-time fluorescent quantitative PCR (RT-qPCR), and Western blot. The results showed that the Cx37 protein was present in sheep oocytes and cumulus cells; the same results were found with respect to GJA4 gene expression. In the gonadotropin-free culture system, compared to the control, significantly higher levels of cAMP as well as Cx37 gene and protein expression were found in sheep COCs following treatment in vitro with Forskolin and IBMX (100 μM and 500 μM)) for 10 min (p < 0.05). Compared to the controls (at 10 or 60 min), cAMP levels in sheep COCs were significantly elevated as a result of Forskolin and IBMX treatment (p < 0.05). Following culturing in vitro for 10 min or 60 min, Forskolin and IBMX treatment can significantly promote Cx37 expression in sheep COCs (p < 0.05), a phenomenon which can be counteracted when the culture media is supplemented with RP-cAMP, a cAMP-specific competitive inhibitor operating through suppression of the protein kinase A (PKA). In summary, this study reports the preliminary regulatory mechanism of cAMP involved in Cx37 expression for the first time, and provides a novel explanation for the interaction between cAMP and GJC communication during sheep COC culturing in vitro. [ABSTRACT FROM AUTHOR]

To develop a cost‐effective microbial cell factory for the production of biofuels and biochemicals, an understanding of tolerant mechanisms is vital for the construction of robust host strains. Here, we characterized a new function of a key metabolic transcription factor named Znf1 and its involvement in stress response in Saccharomyces cerevisiae to enhance tolerance to advanced biofuel, isobutanol. RNA‐sequencing analysis of the wild‐type versus the znf1Δ deletion strains in glucose revealed a new role for transcription factor Znf1 in the pentose phosphate pathway (PPP) and energy generation. The gene expression analysis confirmed that isobutanol induces an adaptive cell response, resulting in activation of ATP1‐3 and COX6 expression. These genes were Znf1 targets that belong to the electron transport chain, important to produce ATPs. Znf1 also activated PPP genes, required for the generation of key amino acids, cellular metabolites, and maintenance of NADP/NADPH redox balance. In glucose, Znf1 also mediated the upregulation of valine biosynthetic genes of the Ehrlich pathway, namely ILV3, ILV5, and ARO10, associated with the generation of key intermediates for isobutanol production. Using S. cerevisiae knockout collection strains, cells with deleted transcriptional regulatory gene ZNF1 or its targets displayed hypersensitivity to isobutanol and acid inhibitors; in contrast, overexpression of ZNF1 enhanced cell survival. Thus, the transcription factor Znf1 functions in the maintenance of energy homeostasis and redox balance at various checkpoints of yeast metabolic pathways. It ensures the rapid unwiring of gene transcription in response to toxic products/by‐products generated during biofuel production. Importantly, we provide a new approach to enhance strain tolerance during the conversion of glucose to biofuels. Take‐away: New insight into transcription of genes related to stress tolerance in yeast.Key transcription factor Znf1 mediated stress response in biofuel production.Activation of PPP, ATP synthesis, Ehrlich pathway by metabolic regulator Znf1.Coordinated control of carbon metabolism, redox balance, and energy generation.ZNF1 enhanced cell tolerance to isobutanol and lignocellulosic inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Background Bacterial RNA polymerase holoenzyme requires sigma70 factors to start transcription by identifying promoter elements. Cyanobacteria possess multiple sigma70 factors to adapt to a wide variety of ecological niches. These factors are grouped into two categories: primary sigma factor initiates transcription of housekeeping genes during normal growth conditions, while alternative sigma factors initiate transcription of specific genes under particular conditions. However, the present classification does not consider the modular organization of their structural domains, introducing therefore multiple functional and structural biases. A comprehensive analysis of this protein family in cyanobacteria is needed to address these limitations. Results We investigated the structure and evolution of sigma70 factors in cyanobacteria, analyzing their modular architecture and variation among unicellular, filamentous, and heterocyst-forming morphotypes. 4,193 sigma70 homologs were found with 59 distinct modular patterns, including six essential and 29 accessory domains, such as DUF6596. 90% of cyanobacteria typically have 5 to 17 sigma70 homologs and this number likely depends on the strain morphotype, the taxonomic order and the genome size. We classified sigma70 factors into 12 clans and 36 families. According to taxonomic orders and phenotypic traits, the number of homologs within the 14 main families was variable, with the A.1 family including the primary sigma factor since this family was found in all cyanobacterial species. The A.1, A.5, C.1, E.1, J.1, and K.1 families were found to be key sigma families that distinguish heterocyst-forming strains. To explain the diversification and evolution of sigma70, we propose an evolutionary scenario rooted in the diversification of a common ancestor of the A1 family. This scenario is characterized by evolutionary events including domain losses, gains, insertions, and modifications. The high occurrence of the DUF6596 domain in bacterial sigma70 proteins, and its association with the highest prevalence observed in Actinobacteria, suggests that this domain might be important for sigma70 function. It also implies that the domain could have emerged in Actinobacteria and been transferred through horizontal gene transfer. Conclusion Our analysis provides detailed insights into the modular domain architecture of sigma70, introducing a novel robust classification. It also proposes an evolutionary scenario explaining their diversity across different taxonomical orders.

Abstract The IVa subfamily of glycine-rich proteins (GRPs) comprises a group of glycine-rich RNA binding proteins referred to as GR-RBPa here. Previous studies have demonstrated functions of GR-RBPa proteins in regulating stress response in plants. However, the mechanisms responsible for the differential regulatory functions of GR-RBPa proteins in different plant species have not been fully elucidated. In this study, we identified and comprehensively studied a total of 34 GR-RBPa proteins from five plant species. Our analysis revealed that GR-RBPa proteins were further classified into two branches, with proteins in branch I being relatively more conserved than those in branch II. When subjected to identical stresses, these genes exhibited intensive and differential expression regulation in different plant species, corresponding to the enrichment of cis-acting regulatory elements involving in environmental and internal signaling in these genes. Unexpectedly, all GR-RBPa genes in branch I underwent intensive alternative splicing (AS) regulation, while almost all genes in branch II were only constitutively spliced, despite having more introns. This study highlights the complex and divergent regulations of a group of conserved RNA binding proteins in different plants when exposed to identical stress conditions. These species-specific regulations may have implications for stress responses and adaptations in different plant species.

Gene expression is known as a phenomenon that shapes human life. This very complex phenomenon is formed from two stages: transcription and translation. In this study, we used the Nose-Hoover thermostat to model the effect of ambient temperature on gene expression since temperature regulates the biological clock of living systems. We have used the Lyapunov exponent approach to investigate the effect of control parameters on gene expression, including the degradation rates of messenger RNA and proteins, and to find critical points (phenomenon boundary limits), mRNA, and protein level boundary values. The rate of degradation in the process of protein synthesis has been investigated with the help of the Lyapunov exponent approach. According to this study, the optimal temperature for the production of mRNA molecules by Escherichia coli bacteria is 306 Kelvin. The study also used the chaos approach to show that the faster the mRNA molecules are degraded, the more they are transcribed, and the more chaotic the system becomes.

Abstract Cyclic adenosine 3’, 5’ monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction.

Objective To investigate the effect of cisplatin treatment on the transcriptional level of human liver cancer cells by conducting transcriptome sequencing analysis after treating human liver cancer cell lines with different concentrations of cisplatin (CDDP). Methods Liver cancer cell lines HepG2 and Huh7 were incubated with cisplatin at different final concentrations of 0,20,50,100 and 200 μmol/L. After 12 hours, cell viability, immunofluorescence and RNA-sequencing(RNA-seq) were performed. Differential gene expression analysis (DEG), KEGG pathway analysis, and protein-protein interaction network analysis were conducted. Results Cisplatin decreased cell viability and increased DNA damage in HepG2,Huh7 cells. Among the genes regulated after cisplatin treatment at different concentrations, 59 genes were commonly up-regulated in both HepG2 and Huh7 cells, while 81 genes were commonly down-regulated. The commonly upregulated genes were mainly enriched in cancer initiation and progression pathways.The 81 commonly down-regulated genes were mainly enriched in Rap1 signaling pathway, Ras signaling pathway, signaling pathways regulating pluripotency of stem cells, axon guidance, and cell adhesion-related pathways. Survival analysis of key nodes in the protein-protein interaction network of commonly upregulated and downregulated genes revealed a significant correlation between high expression of Jun proto-oncogene, AP-1 transcription factor subunit (JUN) and prolonged patient survival and a significant correlation between low expression of growth arrest and DNA damage inducible alpha (GADD45A) and prolonged patient survival. Conclusions The study revealed common transcriptional changes in liver cancer cells under cisplatin treatment. Differential expression of JUN and GADD45A is a potential core mechanism to explain drug resistance. This conclusion provides some important prognostic indicators for clinical treatment.

The Eaf6 protein, a conserved component of the NuA4 and NuA3 complexes in yeast and MOZ/MORF complexes in humans, plays crucial roles in transcriptional activation, gene regulation, and cell cycle control. Despite its significance in other organisms, the functional role of Eaf6 in entomopathogenic fungi (EPF) remained unexplored. Here, we investigate the function of BbEaf6, the Eaf6 homolog in the entomopathogenic fungus Beauveria bassiana. We demonstrate that BbEaf6 is predominantly localized in nuclei, similar to its counterpart in other fungi. Deletion of BbEaf6 resulted in delayed conidiation, reduced conidial yield, and altered conidial properties. Transcriptomic analysis revealed dysregulation of the genes involved in asexual development and cell cycle progression in the ΔBbEaf6 mutant. Furthermore, the ΔBbEaf6 mutant exhibited decreased tolerance to various stresses, including ionic stress, cell wall perturbation, and DNA damage stress. Notably, the ΔBbEaf6 mutant displayed attenuated virulence in insect bioassays, accompanied by dysregulation of genes associated with cuticle penetration and haemocoel infection. Overall, our study elucidates the multifaceted role of BbEaf6 in stress response, development, and virulence in B. bassiana, providing valuable insights into the molecular mechanisms governing fungal pathogenesis and potential targets for pest management strategies.

Background: Bacterial RNA polymerase holoenzyme requires sigma70 factors to start transcription by identifying promoter elements. Cyanobacteria possess multiple sigma70 factors to adapt to a wide variety of ecological niches. These factors are grouped into two categories: primary sigma factor initiates transcription of housekeeping genes during normal growth conditions, while alternative sigma factors initiate transcription of specific genes under particular conditions. However, the present classification does not consider the modular organization of their structural domains, introducing therefore multiple functional and structural biases. A comprehensive analysis of this protein family in cyanobacteria is needed to address these limitations. Results: We investigated the structure and evolution of sigma70 factors in cyanobacteria, analyzing their modular architecture and variation among unicellular, filamentous, and heterocyst-forming morphotypes. 4,193 sigma70 homologs were found with 59 distinct modular patterns, including six essential and 29 accessory domains, such as DUF6596. 90% of cyanobacteria typically have 5 to 17 sigma70 homologs and this number likely depends on the strain morphotype, the taxonomic order and the genome size. We classified sigma70 factors into 12 clans and 36 families. According to taxonomic orders and phenotypic traits, the number of homologs within the 14 main families was variable, with the A.1 family including the primary sigma factor since this family was found in all cyanobacterial species. The A.1, A.5, C.1, E.1, J.1, and K.1 families were found to be key sigma families that distinguish heterocyst-forming strains. To explain the diversification and evolution of sigma70, we propose an evolutionary scenario rooted in the diversification of a common ancestor of the A1 family. This scenario is characterized by evolutionary events including domain losses, gains, insertions, and modifications. The high occurrence of the DUF6596 domain in bacterial sigma70 proteins, and its association with the highest prevalence observed in Actinobacteria, suggests that this domain might be important for sigma70 function. It also implies that the domain could have emerged in Actinobacteria and been transferred through horizontal gene transfer. Conclusion: Our analysis provides detailed insights into the modular domain architecture of sigma70, introducing a novel robust classification. It also proposes an evolutionary scenario explaining their diversity across different taxonomical orders. [ABSTRACT FROM AUTHOR]

Aim: Incorporating non-bloat legumes into grass pastures can reduce enteric methane and alter cattle urinary urea N output by increasing protein intake. Deposition of high urea N urine influences soil N-cycling microbes and potentially N2O production. We studied how urine urea N concentration affects soil nitrifier and denitrifier abundances, activities, and N2O production. Methods: 15N13C-labelled urea dissolved in cattle urine was added at 3.5 and 7.0 g L−1 to soils from a grazed, non-bloat legume pasture and incubated under controlled conditions. CO2, N2O, 13C-CO2, and 15N-N2O production were quantified over 240 h, along with nitrifier and denitrifier N-cycling genes and mRNA transcripts. Results: High urea urine increased total N2O relative to the control; low urea was not significantly different from the control or the high urea treatment. As a result, N2O-N emission factors were not significantly different between the low urea treatment (1.17%) and high urea treatment (0.94%). Doubling urea concentration doubled CO2-Curea and N2O-Nurea but not total N2O-N. Urine addition initially inhibited then increased AOB transcripts and gene abundances. nirK and nirS transcript abundances indicated that denitrification by ammonia oxidizers and/or heterotrophic denitrifiers dominated N2O production. Urine addition increased nosZ-II vs. nosZ-I transcripts, improving soil N2O reduction potential. Conclusion: Characterizing this interplay between nitrifiers and denitrifiers improves the understanding of urine patch N2O sinks and source dynamics. This mechanistic information helps to explain the constrained short-term N2O emissions observed in response to excess urine N excretion from cattle consuming high protein diets, e.g. non-bloat legumes. [ABSTRACT FROM AUTHOR]

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell- specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage- specific differentiation of mouse T- helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1- Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell--mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17- related inflammatory diseases, such as ulcerative colitis. [ABSTRACT FROM AUTHOR]

While flocculation has demonstrated its efficacy in enhancing yeast robustness and ethanol production, its potential application for lactic acid fermentation remains largely unexplored. Our study examined the differences between flocculating and nonflocculating Saccharomyces cerevisiae strains in terms of their metabolic dynamics when incorporating an exogenous lactic acid pathway, across varying cell densities and in the presence of lignocellulose‐derived byproducts. Comparative gene expression profiles revealed that cultivating a nonflocculant strain at higher cell density yielded a substantial upregulation of genes associated with glycolysis, energy metabolism, and other key pathways, resulting in elevated levels of fermentation products. Meanwhile, the flocculating strain displayed an inherent ability to sustain high glycolytic activity regardless of the cell density. Moreover, our investigation revealed a significant reduction in glycolytic activity under chemical stress, potentially attributable to diminished ATP supply during the energy investment phase. Conversely, the formation of flocs in the flocculating strain conferred protection against toxic chemicals present in the medium, fostering more stable lactic acid production levels. Additionally, the distinct flocculation traits observed between the two examined strains may be attributed to variations in the nucleotide sequences of the flocculin genes and their regulators. This study uncovers the potential of flocculation for enhanced lactic acid production in yeast, offering insights into metabolic mechanisms and potential gene targets for strain improvement. Take‐away: Increasing cell density enhances glycolysis and energy metabolism.Lactic acid generation in flocculent yeast is less dependent on cell density.Flocculation provides protection against acid and other chemical stresses. [ABSTRACT FROM AUTHOR]

Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of cisplatin treatment on the transcriptional level of human liver cancer cells by conducting transcriptome sequencing analysis after treating human liver cancer cell lines with different concentrations of cisplatin (CDDP). Methods Liver cancer cell lines HepG2 and Huh7 were incubated with cisplatin at different final concentrations of 0,20,50,100 and 200 μmol/L. After 12 hours, cell viability, immunofluorescence and RNA-sequencing(RNA-seq) were performed. Differential gene expression analysis (DEG), KEGG pathway analysis, and protein-protein interaction network analysis were conducted. Results Cisplatin decreased cell viability and increased DNA damage in HepG2,Huh7 cells. Among the genes regulated after cisplatin treatment at different concentrations, 59 genes were commonly up-regulated in both HepG2 and Huh7 cells, while 81 genes were commonly down-regulated. The commonly upregulated genes were mainly enriched in cancer initiation and progression pathways.The 81 commonly down-regulated genes were mainly enriched in Rap1 signaling pathway, Ras signaling pathway, signaling pathways regulating pluripotency of stem cells, axon guidance, and cell adhesion-related pathways. Survival analysis of key nodes in the protein-protein interaction network of commonly upregulated and downregulated genes revealed a significant correlation between high expression of Jun proto-oncogene, AP-1 transcription factor subunit (JUN) and prolonged patient survival and a significant correlation between low expression of growth arrest and DNA damage inducible alpha (GADD45A) and prolonged patient survival. Conclusions The study revealed common transcriptional changes in liver cancer cells under cisplatin treatment. Differential expression of JUN and GADD45A is a potential core mechanism to explain drug resistance. This conclusion provides some important prognostic indicators for clinical treatment. [ABSTRACT FROM AUTHOR]

Farmland soil organisms frequently encounter pesticide mixtures presented in their living environment. However, the underlying toxic mechanisms employed by soil animals to cope with such combined pollution have yet to be explored. This investigation aimed to reveal the changes in cellular and mRNA levels under chlorpyrifos (CPF) and lambda-cyhalothrin (LCT) co-exposures in earthworms (Eisenia fetida). Results exhibited that the combination of CPF and LCT triggered an acute synergistic influence on the animals. Most exposures resulted in significant alterations in the activities of total superoxide dismutase (T-SOD), copper/zinc superoxide dismutase (Cu/Zn-SOD), caspase 3, and carboxylesterase (CarE) compared to the basal level. Moreover, when exposed to chemical mixtures, the transcription levels of four genes [heat shock protein 70 (hsp70), gst, sod, and calreticulin (crt)] also displayed more pronounced changes compared with their individual exposures. These changes in determined parameters indicated the occurrence of oxidative stress, cell death, detoxification dysfunction, and endoplasmic reticulum damage after co-exposure to CPF and LCT in E. fetida. The comprehensive examination of mixture toxicities of CPF and LCT at different endpoints would help to understand the overall toxicity they cause to soil invertebrates. The augmented deleterious effect of these pesticides in a mixture suggested that mixture toxicity assessment was necessary for the safety evaluation and application of pesticide mixtures.

Simple Summary: The complex mode of gene expression regulation is a key reason underlying the biological heterogeneity and clinical diversity of malignant gliomas. In particular, high variabilities of gene expression are associated with alternative RNA splicing, a mechanism that generates the transcripts of different structures and functions from the same gene. Protein kinases of the DYRK and CLK families are part of the splicing regulation machinery; therefore, pharmacological targeting of these enzymes in gliomas is therapeutically relevant. We demonstrate that the pyrido[3,4-g]quinazoline scaffold is a source of compounds with differential inhibitory efficacy against individual DYRK and CLK enzymes. Our in silico calculations and omics experiments showed that a single chemical substitution in the scaffold can change the kinase inhibitory profile. This modification yielded the splicing antagonist with a high cytotoxic potency against patient-derived glioma cells. Serine-threonine protein kinases of the DYRK and CLK families regulate a variety of vital cellular functions. In particular, these enzymes phosphorylate proteins involved in pre-mRNA splicing. Targeting splicing with pharmacological DYRK/CLK inhibitors emerged as a promising anticancer strategy. Investigation of the pyrido[3,4-g]quinazoline scaffold led to the discovery of DYRK/CLK binders with differential potency against individual enzyme isoforms. Exploring the structure–activity relationship within this chemotype, we demonstrated that two structurally close compounds, pyrido[3,4-g]quinazoline-2,10-diamine 1 and 10-nitro pyrido[3,4-g]quinazoline-2-amine 2, differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound 1, compound 2 efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of 1 and 2 with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of 2 with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with 2 revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, 2 affected the genes that perform critical functions for cancer cells including DNA damage response, p53 signaling and transcription. Altogether, these results provide a mechanistic basis for the therapeutic efficacy of 2 previously demonstrated in in vivo GBM models. [ABSTRACT FROM AUTHOR]

The heart undergoes a dynamic maturation process following birth, in response to a wide range of stimuli, including both physiological and pathological cues. This process entails substantial re-programming of mitochondrial energy metabolism coincident with the emergence of specialized structural and contractile machinery to meet the demands of the adult heart. Many components of this program revert to a more "fetal" format during development of pathological cardiac hypertrophy and heart failure. In this review, emphasis is placed on recent progress in our understanding of the transcriptional control of cardiac maturation, encompassing the results of studies spanning from in vivo models to cardiomyocytes derived from human stem cells. The potential applications of this current state of knowledge to new translational avenues aimed at the treatment of heart failure is also addressed. [ABSTRACT FROM AUTHOR]

Wnt16 is expressed in bone and arteries, and maintains bone mass in mice and humans, but its role in cardiovascular physiology is unknown. We show that Wnt16 protein accumulates in murine and human vascular smooth muscle (VSM). WNT16 genotypes that convey risk for bone frailty also convey risk for cardiovascular events in the Dallas Heart Study. Murine Wnt16 deficiency, which causes postnatal bone loss, also reduced systolic blood pressure. Electron microscopy demonstrated abnormal VSM mitochondrial morphology in Wnt16-null mice, with reductions in mitochondrial respiration. Following angiotensin-II (AngII) infusion, thoracic ascending aorta (TAA) dilatation was greater in Wnt16 −/− vs Wnt16+/+ mice (LDLR −/− background). Acta2 (vascular smooth muscle alpha actin) deficiency has been shown to impair contractile phenotype and worsen TAA aneurysm with concomitant reductions in blood pressure. Wnt16 deficiency reduced expression of Acta2 , SM22 (transgelin), and other contractile genes, and reduced VSM contraction induced by TGFβ. Acta2 and SM22 proteins were reduced in Wnt16 −/− VSM as was Ankrd1, a prototypic contractile target of Yap1 and Taz activation via TEA domain (TEAD)-directed transcription. Wnt16 −/− VSM exhibited reduced nuclear Taz and Yap1 protein accumulation. SiRNA targeting Wnt16 or Taz, but not Yap1, phenocopied Wnt16 deficiency, and Taz siRNA inhibited contractile gene upregulation by Wnt16. Wnt16 incubation stimulated mitochondrial respiration and contraction (reversed by verteporfin, a Yap/Taz inhibitor). SiRNA targeting Taz inhibitors Ccm2 and Lats1/2 mimicked Wnt16 treatment. Wnt16 stimulated Taz binding to Acta2 chromatin and H3K4me3 methylation. TEAD cognates in the Acta2 promoter conveyed transcriptional responses to Wnt16 and Taz. Wnt16 regulates cardiovascular physiology and VSM contractile phenotype, mediated via Taz signaling. [ABSTRACT FROM AUTHOR]

Summary: COLD is a major naturally occurring stress that usually causes complex symptoms and severe yield loss in crops. R‐loops function in various cellular processes, including development and stress responses, in plants. However, how R‐loops function in COLD responses is largely unknown in COLD susceptible crops like rice (Oryza sativa L.).We conducted DRIP‐Seq along with other omics data (RNA‐Seq, DNase‐Seq and ChIP‐Seq) in rice with or without COLD treatment.COLD treatment caused R‐loop reprogramming across the genome. COLD‐biased R‐loops had higher GC content and novel motifs for the binding of distinct transcription factors (TFs). Moreover, R‐loops can directly/indirectly modulate the transcription of a subset of COLD‐responsive genes, which can be mediated by R‐loop overlapping TF‐centered or cis‐regulatory element‐related regulatory networks and lncRNAs, accounting for c. 60% of COLD‐induced expression of differential genes in rice, which is different from the findings in Arabidopsis. We validated two R‐loop loci with contrasting (negative/positive) roles in the regulation of two individual COLD‐responsive gene expression, as potential targets for enhanced COLD resistance.Our study provides detailed evidence showing functions of R‐loop reprogramming during COLD responses and provides some potential R‐loop loci for genetic and epigenetic manipulation toward breeding of rice varieties with enhanced COLD tolerance. [ABSTRACT FROM AUTHOR]

Decidualization of endometrial stroma is a key step in embryo implantation and its abnormality often leads to pregnancy failure. Stromal decidualization is a very complex process that is co‐regulated by estrogen, progesterone and many local factors. The signaling protein SHP2 encoded by PTPN11 is dynamically expressed in decidualized endometrial stroma and mediates and integrates various signals to govern the decidualization. In the present study, we investigate the mechanism of PTPN11 gene transcription. Estrogen, progesterone and cAMP co‐induced decidualization of human endometrial stromal cell in vitro, but only progesterone and cAMP induced SHP2 expression. Using the luciferase reporter, we refined a region from −229 bp to +1 bp in the PTPN11 gene promoter comprising the transcriptional core regions that respond to progesterone and cAMP. Progesterone receptor (PGR) and cAMP‐responsive element‐binding protein 1 (CREB1) were predicted to be transcription factors in this core region by bioinformatic methods. The direct binding of PGR and CREB1 on the PTPN11 promoter was confirmed by electrophoretic mobility and chromatin immunoprecipitation in vitro. Knockdown of PGR and CREB1 protein significantly inhibited the expression of SHP2 induced by medroxyprogesterone acetate and cAMP. These results demonstrate that transcription factors PGR and CREB1 bind to the PTPN11 promoter to regulate the expression of SHP2 in response to decidual signals. Our results explain the transcriptional expression mechanism of SHP2 during decidualization and promote the understanding of the mechanism of decidualization of stromal cells. [ABSTRACT FROM AUTHOR]

Reprograming of chromatin structures and changes in gene expression are critical for plant male gamete development, and epigenetic marks play an important role in these processes. Histone variant H3.3 is abundant in euchromatin and is largely associated with transcriptional activation. The precise function of H3.3 in gamete development remains unclear in plants. Here, we report that H3.3 is abundantly expressed in Arabidopsis anthers and its knockout mutant h3.3–1 is sterile due to male sterility. Transcriptome analysis of young inflorescence has identified 2348 genes downregulated in h3.3–1 mutant, among which 1087 target genes are directly bound by H3.3, especially at their 3ʹ ends. As a group, this set of H3.3 targets is enriched in the reproduction-associated processes including male gamete generation, pollen sperm cell differentiation and pollen tube growth. The function of H3.3 in male gamete development is dependent on the Anti-Silencing Factor 1A/1B (ASF1A/1B)-Histone regulator A (HIRA)-mediated pathway. Our results suggest that ASF1A/1B-HIRA-mediated H3.3 deposition at its direct targets for transcription activation forms the regulatory networks responsible for male gamete development. [ABSTRACT FROM AUTHOR]

In Daphnia magna, 20-hydroecdysone (20E) is the main molting hormone and its metabolism is of interest to identify new biomarkers of exposure to contaminants. The present study aimed to (i) assess baseline levels of 20E and transcription levels of four related-genes (shade, neverland, ultraspiracle, and ecdysteroid receptor); and (ii) evaluate effects in D. magna after 21 days of exposure to fenarimol (anti-ecdysteroid) and a mixture of gemfibrozil and clofibric acid (lipid-lowering drugs) at sublethal concentrations. Endpoints included transcription of the target genes and quantification of 20E, mortality, and reproduction of daphnids. Baseline results showed that average responses were relatively similar and did not vary more than 2-fold. However, intra-day variation was generally high and could be explained by sampling individuals with slightly different stages of their development. Exposure tests indicated a significant decrease in daphnid reproduction following chronic exposure to a concentration of 565 μg/L of fenarimol. However, no difference was observed between the control and exposed groups for any of the investigated genes, nor for the levels of 20E after 21 days of exposure. Following exposition to gemfibrozil and clofibric acid at 1 μg/L, no changes were observed for the measured parameters. These results suggest that changes in transcription levels of the target genes and concentrations of 20E may not be sensitive endpoints that can be used as biomarkers of sublethal exposure to the target compounds in D. magna. Measuring multiple time points instead of a single measure as well as additional molecular endpoints obtained from transcriptomic and metabolomic studies could afford more insights on the changes occurring in exposed daphnids to lipid-altering compounds and identify efficient biomarkers of sublethal exposure. [ABSTRACT FROM AUTHOR]

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27 -related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1–45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27 -related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27 -related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3 (GSK3) signaling plays important and broad roles in regulating neural development in vitro and in vivo. Here, we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field. Overall, current evidence indicates that GSK3β signaling serves as an important downstream mediator of the PI3K–AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway. Specifically, the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation, whereas GSK3β signaling might be involved in regulating N 6-methyladenosine mRNA methylation-mediated, cap-independent protein translation. In addition, GSK3 signaling also plays a key role in reshaping the neuronal transcriptomic landscape during neural regeneration. Finally, we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets. Together, we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo. [ABSTRACT FROM AUTHOR]

Abstract Background Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain’s inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. Methods Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. Results Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. Conclusions GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

Embryonic morphogenesis is strictly dependent on tight spatiotemporal control of developmental gene expression, which is typically achieved through the concerted activity of multiple enhancers driving cell type-specific expression of a target gene. Mammalian genomes are organized in topologically associated domains, providing a preferred environment and framework for interactions between transcriptional enhancers and gene promoters. While epigenomic profiling and three-dimensional chromatin conformation capture have significantly increased the accuracy of identifying enhancers, assessment of subregional enhancer activities via transgenic reporter assays in mice remains the gold standard for assigning enhancer activity in vivo. Once this activity is defined, the ideal method to explore the functional necessity of a transcriptional enhancer and its contribution to target gene dosage and morphological or physiological processes is deletion of the enhancer sequence from the mouse genome. Here we present detailed protocols for efficient introduction of enhancer-reporter transgenes and CRISPR-mediated genomic deletions into the mouse genome, including a step-by-step guide for pronuclear microinjection of fertilized mouse eggs. We provide instructions for the assembly and genomic integration of enhancer-reporter cassettes that have been used for validation of thousands of putative enhancer sequences accessible through the VISTA enhancer browser, including a recently published method for robust site-directed transgenesis at the H11 safe-harbor locus. Together, these methods enable rapid and large-scale assessment of enhancer activities and sequence variants in mice, which is essential to understand mammalian genome function and genetic diseases.

This scientific research article titled "NLRP3 inflammasome activation and cell death" explores the activation of the NLRP3 inflammasome, a protein complex involved in the immune response, and its role in cell death. The authors discuss the mechanisms and signaling pathways associated with NLRP3 inflammasome activation and its implications in various diseases. This article provides valuable insights for researchers studying inflammation and cell death processes. [Extracted from the article]

ABSTRACTBeauveria bassiana is a widely used entomopathogenic fungus in insect biological control applications. In this study, we investigated the role of two sirtuin homologs, BbHst3 and BbHst4, in the biological activities and pathogenicity of B. bassiana. Our results showed that deletion of BbHst3 and/or BbHst4 led to impaired sporulation, reduced (~50%) conidial production, and decreased tolerance to various stresses, including osmotic, oxidative, and cell wall-disturbing agents. Moreover, BbHst4 plays dominant roles in histone H3-K56 acetylation and DNA damage response, while BbHst3 is more responsible for maintaining cell wall integrity. Transcriptomic analyses revealed significant changes (>1,500 differentially expressed genes) in gene expression patterns in the mutant strains, particularly in genes related to secondary metabolism, detoxification, and transporters. Furthermore, the ΔBbHst3, ΔBbHst4, and ΔBbHst3ΔBbHst4 strains exhibited reduced virulence in insect bioassays, with decreased (~20%) abilities to kill insect hosts through topical application and intra-hemocoel injection. These findings highlight the crucial role of BbHst3 and BbHst4 in sporulation, DNA damage repair, cell wall integrity, and fungal infection in B. bassiana. Our study provides new insights into the regulatory mechanisms underlying the biological activities and pathogenicity of B. bassiana and emphasizes the potential of targeting sirtuins for improving the efficacy of fungal biocontrol agents.IMPORTANCESirtuins, as a class of histone deacetylases, have been shown to play important roles in various cellular processes in fungi, including asexual development, stress response, and pathogenicity. By investigating the functions of BbHst3 and BbHst4, we have uncovered their critical contributions to important phenotypes in Beauveria bassiana. Deletion of these sirtuin homologs led to reduced conidial yield, increased sensitivity to osmotic and oxidative stresses, impaired DNA damage repair processes, and decreased fungal virulence. Transcriptomic analyses showed differential expression of numerous genes involved in secondary metabolism, detoxification, transporters, and virulence-related factors, potentially uncovering new targets for manipulation and optimization of fungal biocontrol agents. Our study also emphasizes the significance of sirtuins as key regulators in fungal biology and highlights their potential as promising targets for the development of novel antifungal strategies.

DNA supercoiling is central to many fundamental processes of living organisms. Its average level along the chromosome and over time reflects the dynamic equilibrium of opposite activities of topoisomerases, which are required to relax mechanical stresses that are inevitably produced during DNA replication and gene transcription. Supercoiling affects all scales of the spatio-temporal organization of bacterial DNA, from the base pair to the large scale chromosome conformation. Highlighted in vitro and in vivo in the 1960s and 1970s, respectively, the first Physical models were proposed concomitantly in order to predict the deformation properties of the double helix. About fifteen years later, polymer physics models demonstrated on larger scales the plectonemic nature and the tree-like organization of supercoiled DNA. Since then, many works have tried to establish a better understanding of the multiple structuring and physiological properties of bacterial DNA in thermodynamic equilibrium and far from equilibrium. The purpose of this essay is to address upcoming challenges by thoroughly exploring the relevance, predictive capacity, and limitations of current physical models, with a specific focus on structural properties beyond the scale of the double helix. We discuss more particularly the problem of DNA conformations, the interplay between DNA supercoiling with gene transcription and DNA replication, its role on nucleoid formation and, finally, the problem of scaling up models. Our primary objective is to foster increased collaboration between physicists and biologists. To achieve this, we have reduced the respective jargon to aminimum and we provide some explanatory background material for the two communities. [ABSTRACT FROM AUTHOR]

Labeling of 5-HT-immunoreactive structures was performed on eye slices of freshwater molluscs Lymnaea stagnalis and Pomacea canaliculata. In the periocular region of both species an increased density of 5-HTergic fibers forming structurally distinct plexuses and partially penetrating into the retina was detected. Transcription of serotonin receptor genes was detected in eye tissues: two types in L. stagnalis and three in P. canaliculata. Its relative level is significantly upregulated compared with central ganglia of the nervous system and tentacles. Additionally transcription of the 5HT transporter gene was recorded in P. canaliculata tissues.The obtained results are discussed in terms of a possible serotonergic mechanism of modulation of processes in the retina of gastropods. [ABSTRACT FROM AUTHOR]

Ionizing radiation (IR) and reactive oxygen species (ROS)-induced oxidative stress can cause damage to cellular biomolecules, including DNA, proteins, and lipids. These harmful effects can compromise essential cellular functions and significantly raise the risk of metabolic dysfunction, accumulation of harmful mutations, genome instability, cancer, accelerated cellular senescence, and even death. Here, we present an investigation of HeLa cancer cells' early response to gamma IR (γ-IR) and oxidative stress after preincubation of the cells with natural extracts of the resurrection plant Haberlea rhodopensis. In light of the superior protection offered by plant extracts against radiation and oxidative stress, we investigated the cellular defence mechanisms involved in such protection. Specifically, we sought to evaluate the molecular effects of H. rhodopensis extract (HRE) on cells subjected to genotoxic stress by examining the components of the redox pathway and quantifying the transcription levels of several critical genes associated with DNA repair, cell cycle regulation, and apoptosis. The influence of HRE on genome integrity and the cell cycle was also studied via comet assay and flow cytometry. Our findings demonstrate that HREs can effectively modulate the cellular response to genotoxic and oxidative stress within the first two hours following exposure, thereby reducing the severity of such stress. Furthermore, we observed the specificity of genoprotective HRE doses depending on the source of the applied genotoxic stress. [ABSTRACT FROM AUTHOR]

The world population is experiencing colossal growth and thus demand for food, leading to an increase in the use of pesticides. Persistent pesticide contamination, such as carbendazim, remains a pressing environmental concern, with potentially long-term impacts on aquatic ecosystems. In the present study, Daphnia magna was exposed to carbendazim (5 µg L−1) for 12 generations, with the aim of assessing gene transcription alterations induced by carbendazim (using a D. magna custom microarray). The results showed that carbendazim caused changes in genes involved in the response to stress, DNA replication/repair, neurotransmission, ATP production, and lipid and carbohydrate metabolism at concentrations already found in the environment. These outcomes support the results of previous studies, in which carbendazim induced genotoxic effects and reproduction impairment (increasing the number of aborted eggs with the decreasing number of neonates produced). The exposure of daphnids to carbendazim did not cause a stable change in gene transcription between generations, with more genes being differentially expressed in the F0 generation than in the F12 generation. This could show some possible daphnid acclimation after 12 generations and is aligned with previous multigenerational studies where few ecotoxicological effects at the individual and populational levels and other subcellular level effects (e.g., biochemical biomarkers) were found. [ABSTRACT FROM AUTHOR]

Chromatin is the carrier of human genetic information, and the transcriptional regulation of genes located on chromatin under different spatial and temporal conditions is closely linked to DNA accessibility and chromatin-associated complexes. Histone chemical modifications like acetylation, methylation, phosphorylation constitute the histone codes which regulate the chromatin accessibility and the association of transcriptional complexes with chromatin, resulting in the activation or repression of gene transcription in real-time. With significant technical enhancement of high-resolution mass spectrometry and the antibody preparation of protein chemical modifications, a series of novel histone acyl-lysine like crotonyl-, lactyl-, succinyl- etc. are identified, significantly expanding the diversity of the histone codes and increasing the complexity of histone code mediated gene transcription. In this review, we overview the dynamic regulation of crotonyl-lysine, lactyl-lysine, succinyl-lysine, isobutyryl-lysine, methacryl-lysine, and isonicotinyl-lysine of histone through the writers, erasers and readers, and further highlight our current understanding about gene transcription mediated by these novel types of histone lysine acylation in various biological content as well as human diseases linked to histone lysine acylation. Finally, the challenge and future prospective of lysine acylation in biology are further outlined. [ABSTRACT FROM AUTHOR]

During the Advanced Plant Habitat experiment 2, radish plants were grown in two successive grow-outs on the International Space Station (ISS) for 27 days each. On days 10, 18, and 24, leaf punch (LP) samples were collected and frozen. At harvest, bulb tissue was sampled with oligo-dT functionalized Solid Phase Gene Extraction (SPGE) probes. The space samples were compared with samples from ground controls (GC) grown at the Kennedy Space Center (KSC) under the same conditions as on the ISS, with notably elevated CO2 (about 2500 ppm), and from lab plants grown under atmospheric CO2 but with light and temperature conditions similar to the KSC control. Genes corresponding to peroxidase (RPP), glucosinolate biosynthesis (GIS), protein binding (CBP), myrosinase (RMA), napin (RSN), and ubiquitin (UBQ) were measured by qPCR. LP from day 24 and bulb samples collected at harvest were compared with RNA-seq data from material that was harvested, frozen, and analyzed after return to Earth. The results showed stable transcription in LP samples in GC but decreasing values in ISS samples during both grow-outs, possibly indicative of stress. SPGE results were similar between GC and ISS samples. However, the RNA-seq analyses showed different transcription profiles than SPGE or LP results, possibly related to localized sampling. RNA-seq of leaf samples showed greater variety than LP data, possibly because of different sampling times. RSN and RPP showed the lowest transcription regardless of method. Temporal analyses showed relatively small changes during plant development in space and in ground controls. This is the first study that compares developmental changes in space-grown plants with ground controls based on a comparison between RNA-seq and qPCR analyses. [ABSTRACT FROM AUTHOR]

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Background: Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. Methods: Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. Results: Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. Conclusions: GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants. [ABSTRACT FROM AUTHOR]