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PLoS Genetics May 2024Exceptions to Mendelian inheritance often highlight novel chromosomal behaviors. The maize Pl1-Rhoades allele conferring plant pigmentation can display inheritance...
Exceptions to Mendelian inheritance often highlight novel chromosomal behaviors. The maize Pl1-Rhoades allele conferring plant pigmentation can display inheritance patterns deviating from Mendelian expectations in a behavior known as paramutation. However, the chromosome features mediating such exceptions remain unknown. Here we show that small RNA production reflecting RNA polymerase IV function within a distal downstream set of five tandem repeats is coincident with meiotically-heritable repression of the Pl1-Rhoades transcription unit. A related pl1 haplotype with three, but not one with two, repeat units also displays the trans-homolog silencing typifying paramutations. 4C interactions, CHD3a-dependent small RNA profiles, nuclease sensitivity, and polyadenylated RNA levels highlight a repeat subregion having regulatory potential. Our comparative and mutant analyses show that transcriptional repression of Pl1-Rhoades correlates with 24-nucleotide RNA production and cytosine methylation at this subregion indicating the action of a specific DNA-dependent RNA polymerase complex. These findings support a working model in which pl1 paramutation depends on trans-chromosomal RNA-directed DNA methylation operating at a discrete cis-linked and copy-number-dependent transcriptional regulatory element.
PubMed: 38814980
DOI: 10.1371/journal.pgen.1011296 -
Cell Reports May 2024Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular...
Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular process of autophagy, is involved in pain processing and is targetable for pain relief. We find that monoallelic deletion of Becn1 increases inflammation-induced mechanical hypersensitivity in male mice. However, in females, loss of Becn1 does not affect inflammation-induced mechanical hypersensitivity. In males, intrathecal delivery of a Beclin 1 activator, tat-beclin 1, reverses inflammation- and nerve injury-induced mechanical hypersensitivity and prevents mechanical hypersensitivity induced by brain-derived neurotrophic factor (BDNF), a mediator of inflammatory and neuropathic pain. Pain signaling pathways converge on the enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. The loss of Becn1 upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. We conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males.
PubMed: 38814784
DOI: 10.1016/j.celrep.2024.114293 -
ELife May 2024Silencing pathways prevent transposable element (TE) proliferation and help to maintain genome integrity through cell division. Silenced genomic regions can be...
Silencing pathways prevent transposable element (TE) proliferation and help to maintain genome integrity through cell division. Silenced genomic regions can be classified as either euchromatic or heterochromatic, and are targeted by genetically separable epigenetic pathways. In plants, the RNA-directed DNA methylation (RdDM) pathway targets mostly euchromatic regions, while CMT DNA methyltransferases are mainly associated with heterochromatin. However, many epigenetic features - including DNA methylation patterning - are largely indistinguishable between these regions, so how the functional separation is maintained is unclear. The linker histone H1 is preferentially localized to heterochromatin and has been proposed to restrict RdDM from encroachment. To test this hypothesis, we followed RdDM genomic localization in an mutant by performing ChIP-seq on the largest subunit, NRPE1, of the central RdDM polymerase, Pol V. Loss of H1 resulted in NRPE1 enrichment predominantly in heterochromatic TEs. Increased NRPE1 binding was associated with increased chromatin accessibility in , suggesting that H1 restricts NRPE1 occupancy by compacting chromatin. However, RdDM occupancy did not impact H1 localization, demonstrating that H1 hierarchically restricts RdDM positioning. H1 mutants experience major symmetric (CG and CHG) DNA methylation gains, and by generating an double mutant, we demonstrate these gains are largely independent of RdDM. However, loss of NRPE1 occupancy from a subset of euchromatic regions in corresponded to the loss of methylation in all sequence contexts, while at ectopically bound heterochromatic loci, NRPE1 deposition correlated with increased methylation specifically in the CHH context. Additionally, we found that H1 similarly restricts the occupancy of the methylation reader, SUVH1, and polycomb-mediated H3K27me3. Together, the results support a model whereby H1 helps maintain the exclusivity of heterochromatin by preventing encroachment from other competing pathways.
Topics: Heterochromatin; Euchromatin; DNA Methylation; Histones; Arabidopsis; Arabidopsis Proteins; Epigenesis, Genetic
PubMed: 38814684
DOI: 10.7554/eLife.89353 -
Psychiatrike = Psychiatriki May 2024Esketamine is a non-selective, competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor in the brain. Through NMDA receptor antagonism, esketamine causes a...
Esketamine is a non-selective, competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor in the brain. Through NMDA receptor antagonism, esketamine causes a transient increase in glutamate release, leading to increases in neurotrophic signaling and restoration of synaptic function in brain regions involved in mood regulation and emotional behavior. Several randomized clinical trials have shown its effectiveness in reducing the symptoms of depression in some people, despite its short-term side effects that include mainly disorientation, dizziness, nausea, and increased blood pressure. In 2019, the United States Food and Drug Administration (FDA) as well as the European Medicines Agency approved the use of esketamine nasal spray in combination with an oral antidepressant for treatment-resistant depression in adults. Our study aimed to evaluate the effectiveness of this new therapeutic proposal in a case series of five Greek patients with treatment- resistant depression. Intranasal esketamine was administered under medical supervision in combination with an oral antidepressant. Depressive symptoms were evaluated at three time points (baseline, end of treatment, and one-year post-treatment) using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Patient Health Questionnaire (PHQ-9), the CGI Clinical Global Impression Scale, and the Perceived Deficits Questionnaire for Depression (PDQ-D). Possible side effects were assessed using the Richmond Suppression Agitation Scale (RASS), the Sheehan Disability Scale (SDS), the CADSS Disruptive States Scale, and a predefined list of adverse events (AEs) and serious adverse events (SAEs). Patients followed an individualized treatment plan for seven to twelve months depending on the achievement of an adequate response. Statistical analysis of the results revealed a significant improvement (p<0.05) on all scales used. All participants maintained their level of improvement at follow-up after twelve months. Adverse effects were found to be mild and tolerable. It is worth noting that significant side effects were reported only by the two patients with comorbid personality disorder. The results, despite limited to a small sample, indicate the positive effect of esketamine on the stable reduction of depressive symptoms among patients with resistant depression, even after the completion of treatment.
PubMed: 38814267
DOI: 10.22365/jpsych.2024.006 -
ELife May 2024Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important...
Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from -null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen-enriched cell population, and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency, and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.
Topics: Animals; Female; Pregnancy; Genomic Imprinting; Mice; Polycomb Repressive Complex 2; Fetal Development; Placenta; Oocytes; Amino Acid Transport System A
PubMed: 38813868
DOI: 10.7554/eLife.81875 -
Turkish Journal of Medical Sciences 2023Cysteine and glycine-rich protein 1 (CSRP1) is involved in the cysteine-rich protein family and is a marker of smooth muscle lineages. In colon cancer, the expression of...
BACKGROUND/AIM
Cysteine and glycine-rich protein 1 (CSRP1) is involved in the cysteine-rich protein family and is a marker of smooth muscle lineages. In colon cancer, the expression of this gene is associated with poor prognosis. In this study, the aim was to reevaluate its prognostic relationship in independent cohorts and explore potential underlying biological processes that are linked to aggressive behavior in tumors with high CSRP1 expression, such as epithelial-to-mesenchymal transition (EMT), stromal fractions in the tumor microenvironment, and consensus molecular subtypes (CMSs).
MATERIALS AND METHODS
RNA sequencing (RNAseq)-, microarray-, and single-cell RNAseq (scRNAseq)-based transcriptomic data were obtained from public databases. The EMT score was calculated based on the expression of E-cadherin and vimentin genes using a previously published method. The stromal score generated by the ESTIMATE method was utilized for the analysis of correlation with the CSRP1 expression. The scRNAseq data were analyzed via the Seurat R package. The immunohistochemistry-based protein level expression of CSRP1 was evaluated using the Human Protein Atlas database.
RESULTS
Lower CSRP1 expression was noted in colon tumors compared to normal colon tissue. Patients with a high CSRP1 expression had shorter recurrence-free, overall, and disease-specific survivals in the GSE39582 and GSE17536 datasets (p < 0.05). The methylation level of the CSRP1 gene was negatively correlated (r = -0.57, p < 0.0001) with CSRP1 expression in The Cancer Genome Atlas colon adenocarcinoma dataset. CSRP1 expression was positively correlated with the expression of mesenchymal markers, EMT score, and stromal score obtained via the ESTIMATE method. CMS4 colon tumors had a significantly higher CSRP1 expression compared to other CMSs. Analysis of the scRNAseq data revealed that CSRP1 was expressed by epithelial cells and cancer-associated fibroblasts in the colorectal tumor microenvironment, which was also confirmed by the protein expression data from the Human Protein Atlas database.
CONCLUSION
CSRP1 expression is associated with CMS4, a more mesenchymal stroma-rich molecular profile, and poor prognosis in colon cancer.
Topics: Humans; Colonic Neoplasms; Prognosis; Epithelial-Mesenchymal Transition; Male; Biomarkers, Tumor; Female; Tumor Microenvironment; Middle Aged; Repressor Proteins; Aged
PubMed: 38813484
DOI: 10.55730/1300-0144.5736 -
Food Chemistry: X Jun 2024Microbial composition plays an important role in the quality and flavor of bacon. The aims of this study were to detect bacterial community succession using...
Microbial composition plays an important role in the quality and flavor of bacon. The aims of this study were to detect bacterial community succession using high-throughput sequencing (HTS) and volatile flavor compound changes using gas chromatography-ion mobility spectrometry (GC-IMS) during the production of Zhenba bacon. The results showed that a total of 70 volatile compounds were detected. Among them, ketones, hydrocarbons, aldehydes, esters and alcohols were the main substances in the curing and smoking stages. In addition, the fungal abundance was greater than the bacterial abundance, and there was obvious succession of the microbial community with changes in fermentation time and processing technology. The main functional bacterial genera in the curing and smoking stages were , and , and the main fungal genera were and . Through correlation analysis, we found that pyrrole, 2-pentanol, methyl isobutyl ketone (MIBK) and ethyl acetate (EA) were significantly correlated with , , and ( < 0.01), and it is speculated that they contribute significantly to flavor formation. The results of this study are helpful for understanding the microbial dynamics and characteristic volatile flavor compounds in Zhenba bacon, and provide new insights into the relationship between microorganisms and flavor through potential correlations.
PubMed: 38813459
DOI: 10.1016/j.fochx.2024.101478 -
Heliyon May 2024In metal-organic frameworks (MOFs), confined space as a chemical nanoreactor is as essential as coordinatively unsaturated metal site catalysis. The properties of MOFs...
In metal-organic frameworks (MOFs), confined space as a chemical nanoreactor is as essential as coordinatively unsaturated metal site catalysis. The properties of MOFs can be adjusted through the incorporation of functional groups and open metal sites in frameworks that can modify the catalytic performance. In this regard, a set of defect-engineered MOFs, Ex-MOF-808(NH, NO, H) and Mix-MOF-808(NH, NO, H), were synthesized by ultrasonic-assisted linker exchange approach (Ex-MOFs) and solvothermal mixing ligand method (Mix-MOFs), respectively. Further, the relationship between the preparation method, structural properties, and catalytic efficiency of the prepared materials in the selective oxidation of methyl phenyl sulfide (MPS) has been investigated. By analyzing zeta potential, it was found that in the exchange method, the amount of defect and functional groups on the surface of MOFs are more than in the mixing method, which also affects the catalytic activity. In our contribution, mix-MOF-808(NO) carrying nitro groups at their organic linkers, which has a well-dispersion of nitro groups at the framework exhibits selective conversion of MPS to sulfone (91 %). Furthermore, the performance of stable heterogeneous catalysts was investigated for three cycles, which demonstrated their great potential for advanced catalytic oxidation.
PubMed: 38813201
DOI: 10.1016/j.heliyon.2024.e31254 -
Heliyon May 2024In the 21st century, cancer remains a serious threat to people's health and has become a prominent public health problem. NFKBIA is involved in the pathological process...
In the 21st century, cancer remains a serious threat to people's health and has become a prominent public health problem. NFKBIA is involved in the pathological process of many diseases including cancer, but its specific role in pan-cancer has not yet been fully elucidated. This study aims to deepen the understanding of cancer pathology by analyzing the potential functions of NFKBIA in pan-cancer. We used TCGA data to analyze differences of expression of NFKBIA in pan-cancer. We explored the prognostic value, clinical relevance, immune relevance, potential biological function, and diagnosis and treatment value of NFKBIA in pan-cancer through bioinformatics analysis. This study found that in pan-cancer, NFKBIA exhibits differences in expression, which correlate with the prognosis, diagnosis, treatment value and clinical and immune parameters. We have identified that Aspirin, Astaxanthin and Bardoxolone methyl are expected to play a potential therapeutic role in pan-cancer. The results of this study will help to improve our understanding of the role and potential mechanism of NFKBIA in cancer pathology, which may provide guidance for cancer-related research and clinical diagnosis and treatment.
PubMed: 38813139
DOI: 10.1016/j.heliyon.2024.e31204 -
Frontiers in Bioengineering and... 2024Methanotrophic bacteria are promising hosts for methane bioconversion to biochemicals or bioproducts. However, due to limitations associated with long genetic...
Methanotrophic bacteria are promising hosts for methane bioconversion to biochemicals or bioproducts. However, due to limitations associated with long genetic manipulation timelines and, lack of choice in genetic tools required for strain engineering, methanotrophs are currently not employed for bioconversion technologies. In this study, a rapid and reproducible electroporation protocol is developed for type 1 methanotroph, using common laboratory solutions, analyzing optimal electroshock voltages and post-shock cell recovery time. Successful reproducibility of the developed method was achieved when different replicative plasmids were assessed on lab adapted vs. wild-type strains (DASS vs. DSM19304). Overall, a ∼ 3-fold decrease in time is reported with use of electroporation protocol developed here, compared to conjugation, which is the traditionally employed approach. Additionally, an inducible (3-methyl benzoate) and a constitutive (sucrose phosphate synthase) promoter is characterized for their strength in driving gene expression.
PubMed: 38812915
DOI: 10.3389/fbioe.2024.1412410