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Evolutionary Applications Jul 2024Anthropogenic climate change has led to globally increasing temperatures at an unprecedented pace and, to persist, wild species have to adapt to their changing world....
Anthropogenic climate change has led to globally increasing temperatures at an unprecedented pace and, to persist, wild species have to adapt to their changing world. We, however, often fail to derive reliable predictions of species' adaptive potential. Genomic selection represents a powerful tool to investigate the adaptive potential of a species, but constitutes a 'blind process' with regard to the underlying genomic architecture of the relevant phenotypes. Here, we used great tit () females from a genomic selection experiment for avian lay date to zoom into this blind process. We aimed to identify the genetic variants that responded to genomic selection and epigenetic variants that accompanied this response and, this way, might reflect heritable genetic variation at the epigenetic level. We applied whole genome bisulfite sequencing to blood samples of individual great tit females from the third generation of bidirectional genomic selection lines for early and late lay date. Genomic selection resulted in differences at both the genetic and epigenetic level. Genetic variants that showed signatures of selection were located within genes mostly linked to brain development and functioning, including (-like). SOX3 is a transcription factor that is required for normal hypothalamo-pituitary axis development and functioning, an essential part of the reproductive axis. As for epigenetic differentiation, the early selection line showed hypomethylation relative to the late selection line. Sites with differential DNA methylation were located in genes important for various biological processes, including gonadal functioning (e.g., MSTN and PIK3CB). Overall, genomic selection for avian lay date provided insights into where within the genome the heritable genetic variation for lay date, on which selection can operate, resides and indicates that some of this variation might be reflected by epigenetic variants.
PubMed: 38948539
DOI: 10.1111/eva.13703 -
Frontiers in Genetics 2024The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the...
The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from conditional knockout animals ( ) targeted to the exocrine pancreatic epithelial cells ( and ), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
PubMed: 38948355
DOI: 10.3389/fgene.2024.1412767 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the roles of histone H3K27me3 methylation and its regulatory enzymes JMJD3 and EZH2 in the differentiation of Th17 cells in ankylosing spondylitis (AS),...
OBJECTIVE
To investigate the roles of histone H3K27me3 methylation and its regulatory enzymes JMJD3 and EZH2 in the differentiation of Th17 cells in ankylosing spondylitis (AS), to unveil their potential involvement in the pathogenesis of AS, and to provide new strategies and targets for the clinical treatment of AS by analyzing the methylation state of H3K27me3 and its interactions with Th17-related factors.
METHODS
A total of 84 AS patients (42 active AS patiens and 42 patients in the stable phase of AS) were enrolled for the study, while 84 healthy volunteers were enrolled as the controls. Blood samples were collected. Peripheral blood mononuclear cells were isolated. ELISA assay was performed to examine Th17 cells and the relevant cytokines IL-21, IL-22, and IL-17. The mRNA expressions of , , and were analyzed by RT-PCR, the protein expressions of RORc, JAK2/STAT3 pathway protein, H3K27me3 and the relevant protease (EZH2 and JMJD3) were determined by Western blot. Correlation between H3K27me3, EZH2 and JMJD3 and the key signaling pathway molecules of Th cell differentiation was analyzed by Pearson correlation analysis.
RESULTS
The mRNA expressions of , , and were significantly higher in the active phase group than those in the stable phase group ( <0.05). The relative grayscale values of H3K27me3 and EZH2 in the active phase group were lower than those of the stable phase group, which were lower than those of the control group, with the differences being statistically significant ( <0.05). The relative grayscale values of JMJD3, RORc, JAK2, pJAK2, STAT3, and pSTAT3 proteins were significantly higher in the active phase group than those in the stable phase group, which were higher than those in the control group (all <0.05). The proportion of Th17 and the expression level of inflammatory factors in the active period group were higher than those in the other two groups (P<0.05). H3K27me3 was negatively correlated with RORc, JAK2, STAT3, and IL-17, JMJD3 was positvely correlated with JAK2, STAT3, and IL-17, and EZH2 was negatively correlated with JAK2, STAT3, and IL-17 (all <0.05).
CONCLUSION
The low expression of H3K27me3 in AS is influenced by the gene loci JMJD3 and EZH2, which can regulate the differentiation of Th17 cells and thus play a role in the pathogenesis and progression of AS.
Topics: Humans; Spondylitis, Ankylosing; Th17 Cells; Jumonji Domain-Containing Histone Demethylases; Cell Differentiation; Histones; STAT3 Transcription Factor; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Interleukin-17; Nuclear Receptor Subfamily 1, Group F, Member 3; Janus Kinase 2; Methylation; Interleukins; Interleukin-22; Male; Female; Adult
PubMed: 38948276
DOI: 10.12182/20240560605 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with... (Review)
Review
Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with infertility exhibit symptoms such as oligospermia, asthenospermia, azoospermia, and compromised sperm quality. Spermatogenesis is a complex and tightly coordinated process of germ cell differentiation, precisely regulated at transcriptional, posttranscriptional, and translational levels to ensure stage-specific gene expression during the development of spermatogenic cells and normal spermiogenesis. N-methyladenosine (mA) stands out as the most prevalent modification on eukaryotic mRNA, playing pivotal roles in various biological processes, including mRNA splicing, transportation, and translation. RNA methylation modification is a dynamic and reversible process primarily mediated by "writers", removed by "erasers", and recognized by "readers". In mammals, the aberrant methylation modification of mA on mRNA is associated with a variety of diseases, including male infertility. However, the precise involvement of disrupted mA modification in the pathogenesis of human male infertility remains unresolved. Intriguingly, a significant correlation has been found between the expression levels of mA regulators in the testis and the severity of sperm concentration, motility, and morphology. Aberrant expression patterns of mA regulatory proteins have been detected in anomalous human semen samples, including those of oligospermia, asthenozoospermia, and azoospermia. Furthermore, the examination of both sperm samples and testicular tissues revealed abnormal mRNA mA modification, leading to reduced sperm motility and concentration in infertile men. Consequently, it is hypothesized that dysregulation of mA modification might serve as an integral link in the mechanism of male infertility. This paper presents a comprehensive review of the recent discoveries regarding the spatial and temporal expression dynamics of mA regulators in testicular tissues and the correlation between deregulated mA regulators and human male infertility. Previous studies predominantly utilized constitutive or conditional knockout animal models for testicular phenotypic investigations. However, gene suppression in additional tissues could potentially influence the testis in constitutive knockout models. Furthermore, considering the compromised spermatogenesis observed in constitutive animals, distinguishing between the indirect effects of gene depletion on testicular development and its direct impact on the spermatogenic process is challenging, due to their intricate relationship. Such confounding factors might compromise the validity of the findings. To address this challenge, an inducible and conditional gene knockout model may serve as a superior approach. To date, nearly all reported studies have concentrated solely on the level changes of mA and its regulators in germs cells, while the understanding of the function of mA modification in testicular somatic cells remains limited. Testicular somatic cells, including peritubular myoid cells, Sertoli cells, and Leydig cells, play indispensable roles during spermatogenesis. Hence, comprehensive exploration of mA modification within these cells as an additional crucial regulatory mechanism is warranted. In addition, exploration into the presence of unique methylation mechanisms or mA regulatory factors within the testes is warranted. To elucidate the role of mA modification in germ cells and testicular somatic cells, detailed experimental strategies need to be implemented. Among them, manipulation of the levels of key enzymes involved in mA methylation and demethylation might be the most effective approach. Moreover, comprehensive analysis of the gene expression profiles involved in various signaling pathways, such as Wnt/β-catenin, Ras/MAPK, and Hippo, in mA-modified germ cells and testicular somatic cells can provide more insight into its regulatory role in the spermatogenesis process. Further research in this area could provide valuable insights for developing innovative strategies to treat male infertility. Finally, considering the mitigation impact of mA imbalance regulation on disease, investigation concerning whether restoring the equilibrium of mA modification regulation can restore normal spermatogenesis function is essential, potentially elucidating the pivotal clinical significance of mA modulation in male infertility.
Topics: Male; Humans; Adenosine; Spermatogenesis; Infertility, Male; RNA, Messenger; Methylation; Animals; Methyltransferases; Spermatozoa; Testis
PubMed: 38948273
DOI: 10.12182/20240560103 -
Cancer Innovation Aug 2024Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor...
BACKGROUND
Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required.
METHODS
The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms.
RESULTS
NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC.
CONCLUSIONS
NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.
PubMed: 38948253
DOI: 10.1002/cai2.122 -
Theranostics 2024Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates...
Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of mA modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. mA modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-β1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing mA modification on and mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-β1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting mA modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.
Topics: Humans; Methyltransferases; Monocytes; Fibrosis; Male; Animals; NF-kappa B; Erythrocytes; Adenosine; Female; Methylation; Mice; Transforming Growth Factor beta1; Cell-Derived Microparticles; Leukocytes, Mononuclear; Angiotensin II; Receptors, Interleukin-8B; Ventricular Remodeling; Myocardium; Nanomedicine
PubMed: 38948064
DOI: 10.7150/thno.95664 -
Frontiers in Oncology 2024Hepatoblastoma (HB) is the most common pediatric hepatic malignancy. Despite the progress in HB treatment, investigating HB pathomechanisms to optimize stratification...
BACKGROUND
Hepatoblastoma (HB) is the most common pediatric hepatic malignancy. Despite the progress in HB treatment, investigating HB pathomechanisms to optimize stratification and therapies remains a focal point to improve the outcome for high-risk patients.
METHODS
Here, we pointed to explore the impact of these mechanisms in HB. An observational study was performed on liver samples from a cohort of 17 patients with a diagnosis of HB and two normal liver samples. The experiments were executed on the Huh6 human HB cell line treated with the FAK inhibitor TAE226.
RESULTS
Our results highlight a significant up-regulation of mRNA and protein expression of FAK in livers from HB with respect to normal livers. The increased protein expression of total and Tyr397 phosphorylated FAK (pTyr397FAK) was significantly correlated with the expression of some epigenetic regulators of histone H3 methylation and acetylation. Of note, the expression of pTyr397FAK, N-methyltransferase enzyme (EZH2) and tri-methylation of the H3K27 residue correlated with tumor size and alpha-fetoprotein (AFP) levels. Finally, TAE226 caused a significant reduction of pTyr397FAK, epigenetic regulators, , , , and , in association with anti-proliferative and pro-apoptotic effects on HB cells.
CONCLUSION
Our results suggest a role of FAK in HB that requires further investigations mainly focused on the exploration of its effective diagnostic and therapeutic translatability.
PubMed: 38947885
DOI: 10.3389/fonc.2024.1397647 -
ACS Omega Jun 2024Microcystins are hepatotoxic cyclic heptapeptides produced by some cyanobacterial species and usually contain the unusual β-amino acid...
Microcystins are hepatotoxic cyclic heptapeptides produced by some cyanobacterial species and usually contain the unusual β-amino acid 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic acid (Adda) at position-5. The full microcystin gene cluster from PCC 7806 has been expressed in . In an earlier study, the engineered strain was shown to produce MC-LR and [d-Asp]MC-LR, the main microcystins reported in cultures of PCC 7806. However, analysis of the engineered strain of using semitargeted liquid chromatography with high-resolution tandem mass spectrometry (LC-HRMS/MS) and thiol derivatization revealed the presence of 15 additional microcystin analogues, including four linear peptide variants and, in total, 12 variants with modifications to the Adda moiety. Four of the Adda-variants lacked the phenyl group at the Adda-terminus, a modification that has not previously been reported in cyanobacteria. Their HRMS/MS spectra contained the product-ion from Adda at / 135.1168, but the commonly observed product-ion at / 135.0804 from Adda-containing microcystins was almost completely absent. In contrast, three of the variants were missing a methyl group between C-2 and C-8 of the Adda moiety, and their LC-HRMS/MS spectra displayed the product-ion from Adda at / 135.0804. However, instead of the product-ion at / 135.1168, these three variants gave product-ions at / 121.1011. These observations, together with spectra from microcystin standards using in-source fragmentation, showed that the product-ion at / 135.1168 found in the HRMS/MS spectra of most microcystins originated from the C-2 to C-8 region of the Adda moiety. Identification of the fragmentation pathways for the Adda side chain will facilitate the detection of microcystins containing modifications in their Adda moieties that could otherwise easily be overlooked with standard LC-MS screening methods. Microcystin variants containing Abu at position-1 were also prominent components of the microcystin profile of the engineered bacterium. Microcystin variants with Abu or without the phenyl group on the Adda side chain were not detected in the original host cyanobacterium. This suggests not only that the microcystin synthase complex may be affected by substrate availability within its host organism but also that it possesses an unexpected degree of biosynthetic flexibility.
PubMed: 38947807
DOI: 10.1021/acsomega.4c03332 -
ACS Omega Jun 2024This study aimed to investigate heterogeneous catalytic filaments of calcium oxide (CaO) for fused deposition modeling three-dimensional (3D) printers. The CaO catalysts...
This study aimed to investigate heterogeneous catalytic filaments of calcium oxide (CaO) for fused deposition modeling three-dimensional (3D) printers. The CaO catalysts were blended with acrylonitrile butadiene styrene (ABS) plastic to form catalytic filaments. A single-screw filament extruder was used to prepare the filaments, following which their mechanical properties, thermal properties, morphology, catalytic characteristics in biodiesel production, and reusability were evaluated. In accordance with the results, a maximum CaO catalyst content of 15 wt % was recommended to be blended in the ABS pellet. The hardness and compressive strength of these catalytic filaments were shown to be improved. Subsequently, the catalytic filaments with the highest CaO content (15 wt %) were used to produce methyl ester from pretreated sludge palm oil through the transesterification process. To determine the recommended conditions for achieving the highest purity of methyl ester in biodiesel, the process parameters were optimized. A methyl ester purity of 96.58 wt % and a biodiesel yield of 79.7 wt % could be achieved under the recommended conditions of a 9.0:1 methanol to oil molar ratio, 75.0 wt % catalytic filament loading, and 4.0 h reaction time. Furthermore, the reusability of the 15 wt % CaO catalytic filaments was evaluated in a batch process with multiple transesterification cycles. The results indicated that the purity of methyl ester dropped to 95.0 wt % only after the fourth cycle. The method used in this study for preparing and characterizing CaO catalytic filaments can potentially serve as a novel approach for constructing biodiesel reactors using 3D printing technology.
PubMed: 38947778
DOI: 10.1021/acsomega.4c03063 -
Heliyon Jun 2024L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various...
L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various ailments. This study aims to comprehensively evaluate the antioxidant, anti-inflammatory, and dermatoprotective properties of essential oil derived from , and thyme honey as well as their combined effects. To unravel the chemical composition, a rigorous GC-MS analysis was conducted. Subsequently, we examined their antioxidant potential through three distinct assays: DPPH●, hydrogen peroxide assay, and xanthine oxidase assay. The anti-inflammatory properties were scrutinized through both in vitro and experiments. Simultaneously, the dermatoprotective efficacy was investigated in vitro by evaluating tyrosinase inhibition. Our findings revealed that pulegone constitutes the predominant compound in essential oil (MPEO), constituting a remarkable 74.82 % of the composition. Significantly, when the essential oil was combined with thym honey, it exhibited superior anti-inflammatory and dermatoprotective effects across all and in vitro tests. Moreover, our in silico molecular docking analysis hinted at the potential role of cyclohexanone, 3-methyl, an element found in the MPEO, in contributing to the observed outcomes. While this study has unveiled promising results regarding the combined in vitro, and in silico biological activities of the essential oil and honey, it is imperative to delve further into the underlying mechanisms through additional experimentation and alternative experimental methods. Understanding these mechanisms in greater detail will not only enhance our comprehension of the therapeutic potential but also pave the way for the development of innovative treatments and applications rooted in the synergy of these natural compounds. Furthermore, it would be advantageous to test different possible combinations using experimental design model. Moreover, it would be better to test the effect of single compounds of MPEO to clearly elucidate their efficiency. MPEO alone or combined with thyme honey may be a useful for the development of novel biopharmaceuticals.
PubMed: 38947443
DOI: 10.1016/j.heliyon.2024.e31922