Linde and Zimmer-Bensch discuss the role of DNA methylation and its writers, DNA methyltransferases DNMT1 and DNMT3A, in regulating essential genes for GABAergic neuronal functions, as well as genes ...of the endocytosis process critical for synaptic neurotransmission. Besides perturbations in neurons, glia pathology also participates in psychiatric disorders (Cotter et al., 2002). Since DNA methylation is critically implicated in many neuropsychiatric diseases, it presents a potential target for treatment (Sales and Joca, 2016; Shirvani-Farsani et al., 2021). Among all these studies, only the correlation between methylation at the BDNF gene locus and antidepressant effects in MDD was reproduced by multiple groups (Januar et al., 2015; Zhou et al.). Since the antidepressant effect of BDNF is well-established in animal studies (Lee and Kim, 2010), this provides evidence for using current animal models (stress-induced depressive-like behaviors in mice and rats) as valid tools for studying mental disorders. MDD is becoming one of the most severe health problems globally (Otte et al., 2016). Besides chronic stress that is well-accepted as top one risk factor for MDD (Breslau and Davis, 1986), other environmental factors, including dietary influences, contribute to the neuropathogenesis of depression (Firth et al., 2020).
Monoubiquitination of H2BK123 (H2BK123ub), catalyzed by Rad6/Bre1, is a transient histone modification with roles in transcription and is essential for establishing H3K4 and H3K79 trimethylations ...(H3K4me3 and H3K79me3). Here, we investigated the chromatin network around H2BK123ub by examining its localization and co-occurrence with its dependent marks as well as the transcription elongation mark H3K36me3 across the genome of Saccharomyces cerevisiae. In yeast, H2BK123ub is removed by the deubiquitinases Ubp8 and Ubp10, but their genomic target regions remain to be determined. Genome-wide maps of H2BK123ub in the absence of Ubp8 and Ubp10 revealed their distinct target loci, which were genomic sites enriched for H3K4me3 and H3K79me3, respectively. We propose an extended model of the H2BK123ub cross-talk by integrating existing relationships with the substrate specificities of Ubp8 and Ubp10 reported here.
The aim of this study was to develop prediction models for total sperm motility, morphological abnormalities and sperm output based on 1,551 ejaculate records of 58 Holstein bulls. The data was ...collected from September 2019 to November 2020 in a single artificial insemination (AI) center located in Eastern Germany. Factors considered for the prediction models include barn climate conditions, semen collector, number of false mounts, libido, semen collection frequency, breed and age (10–74 months). In this study, the prediction models Lasso, Group Lasso and Gradient Boosting were evaluated. The best model for each sperm quality parameter was chosen using cross validation. The models were estimated with five algorithms for sperm motility and sperm morphology and three algorithms for the number of total sperm per ejaculate (sperm output). For sperm motility and morphology a binary classification algorithm was applied, reaching an accuracy of over 80% for all models. For sperm output, no such classification was used and the only variable selected by all three algorithms was age. Furthermore, for sperm morphology, climate variables were frequently selected. Additionally, network diagrams from Group Lasso show the interdependencies between the major variable groups influencing sperm motility and morphology. In conclusion, the implementation of such prediction tools could help AI centers to optimize management factors and stabilize bull semen production in the future.
•Three different machine lesarning tools were used predicting sperm quality of 58 Holstein bulls.•Prediction accuracy for sperm motility and morphology was 80% for all models.•Prediction performance is better in the models that include the bull-specific effect.
Antibiotics are of great importance in boar semen extenders to ensure long shelf life of spermatozoa and to reduce transmission of pathogens into the female tract. However, the use of antibiotics ...carries a risk of developing resistant bacterial strains in artificial insemination laboratories and their spread via artificial insemination. Development of multiresistant bacteria is a major concern if mixtures of antibiotics are used in semen extenders. Minimal contamination prevention techniques and surveillance of critical hygiene control points proved to be efficient in reducing bacterial load and preventing development of antibiotic resistance. Nevertheless, novel antimicrobial concepts are necessary for efficient bacterial control in extended boar semen with a minimum risk of evoking antibiotic resistance. Enhanced efforts have been made in recent years in the design and use of antimicrobial peptides (AMPs) as alternatives to conventional antibiotics. The male genital tract harbors a series of endogenic substances with antimicrobial activity and additional functions relevant to the fertilization process. However, exogenic AMPs often exert dose- and time-dependent toxic effects on mammalian spermatozoa. Therefore, it is important that potential newly designed AMPs have only minor impacts on eukaryotic cells. Recently, synthetic magainin derivatives and cyclic hexapeptides were tested for their application in boar semen preservation. Bacterial selectivity, proteolytic stability, thermodynamic resistance, and potential synergistic interaction with conventional antibiotics propel predominantly cyclic hexapeptides into highly promising, leading candidates for further development in semen preservation. The time scale for the development of resistant pathogens cannot be predicted at this moment.
Purpose
In Sub-Saharan Africa, manifestations of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are commonly seen in human immunodeficiency virus-infected patients receiving ...nevirapine-based antiretroviral therapy and/or cotrimoxazole. These patients often face severe ocular complications that lead to moderate to severe visual impairment or blindness.
Methods
Review of the current literature, illustrated by retrospective hospital-based case series: Eight patients at Lions Sight First Eye Hospital, Blantyre, Malawi with severe ocular complications like severe cicatrizing conjunctivitis with symblephara, corneal punctate erosions, corneal vascularization, and corneal ulceration are illustrated after the diagnosis of SJS/TEN.
Results
Light perception was reported in six (12 eyes) of them; two patients (4 eyes) had moderate visual impairment (6/36 and 6/18). In one patient, eye problems started after therapy with cotrimoxazole; in seven after therapy, with antiretroviral therapy.
Conclusion
SJS/TEN in Sub Saharan Africa correlates significantly with moderate visual impairment up to blindness. Early recognition of eye complications and involvement of ophthalmologists in the acute stage, early treatment with local steroids, and close monitoring for up to 6 months after the acute phase are crucial. Severe ocular complications seem to be more severe in dark skin phototype.
Elevated alpha-synuclein (SNCA) gene expression is associated with transcriptional deregulation and increased risk of Parkinson's disease, which may be partially ameliorated by environmental ...enrichment. At the molecular level, there is emerging evidence that excess alpha-synuclein protein (aSyn) impacts the epigenome through direct and/or indirect mechanisms. However, the extents to which the effects of both aSyn and the environment converge at the epigenome and whether epigenetic alterations underpin the preventive effects of environmental factors on transcription remain to be elucidated. Here, we profiled five DNA and histone modifications in the hippocampus of wild-type and transgenic mice overexpressing human SNCA. Mice of each genotype were housed under either standard conditions or in an enriched environment (EE) for 12 months. SNCA overexpression induced hippocampal CpG hydroxymethylation and histone H3K27 acetylation changes that associated with genotype more than environment. Excess aSyn was also associated with genotype- and environment-dependent changes in non-CpG (CpH) DNA methylation and H3K4 methylation. These H3K4 methylation changes included loci where the EE ameliorated the impacts of the transgene as well as loci resistant to the effects of environmental enrichment in transgenic mice. In addition, select H3K4 monomethylation alterations were associated with changes in mRNA expression. Our results suggested an environment-dependent impact of excess aSyn on some functionally relevant parts of the epigenome, and will ultimately enhance our understanding of the molecular etiology of Parkinson's disease and other synucleinopathies.
•SNCA overexpression was associated with altered DNA and histone modifications.•SNCA overexpression and environmental enrichment jointly influenced H3K4 methylation.•Environmental enrichment dampened select H3K4me1 and gene expression changes.
MLL rearrangements play a crucial role in leukemogenesis and comprise a poor prognosis. Therefore, new treatment strategies are urgently needed. We used the CRISPR/Cas9 system to generate an ...innovative leukemia model based on 100% pure MLL-AF4 or -AF9 rearranged cells derived from umbilical cord blood with indefinite growth in cell culture systems. Our model shared phenotypical, morphological and molecular features of patient cells faithfully mimicking the nature of the disease. Thus, it serves as a fundamental basis for pharmacological studies: inhibition of histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is one specific therapeutic approach currently tested in clinical trials. However, success was limited by restricted response warranting further investigation of drug combinations. Recently, it has been shown that the inhibition of protein arginine methyltransferase 5 (PRMT5) exhibits anti-tumoral activity against human cell lines and in MLL mouse models. Here, we used DOT1L and PRMT5 inhibitors in our human MLL-rearranged model demonstrating dose-dependent reduced proliferation, impairment of cell cycle, increasing differentiation, apoptosis, downregulation of target genes and sensitization to chemotherapy. Strikingly, the combination of both compounds led to synergistic anti-tumoral effects. Our study provides a strong rationale for novel targeted combination therapies to improve the outcome of MLL-rearranged leukemias.
The aim of this study was to investigate the association between processed and other meat intake and incidence of Type 2 diabetes in a large cohort of women.
Incident cases of Type 2 diabetes were ...identified during 8 years of follow-up in a prospective cohort study of 91246 U.S. women aged 26 to 46 years and being free of diabetes and other major chronic diseases at baseline in 1991.
We identified 741 incident cases of confirmed Type 2 diabetes during 716276 person-years of follow-up. The relative risk adjusted for potential non-dietary confounders was 1.91 (95% CI: 1.42-2.57) in women consuming processed meat five times or more a week compared with those consuming processed meat less than once a week ( p<0.001 for trend). Further adjustment for intakes of magnesium, cereal fibre, glycaemic index, and caffeine or for a Western dietary pattern did not appreciably change the results and associations remained strong after further adjustment for fatty acid and cholesterol intake. Frequent consumption of bacon, hot dogs, and sausage was each associated with an increased risk of diabetes. While total red meat (beef or lamb as main dish, pork as main dish, hamburger, beef, pork or lamb as sandwich or mixed dish) intake was associated with an increased risk of diabetes, this association was attenuated after adjustment for magnesium, cereal fiber, glycaemic index, and caffeine (relative risk: 1.44; 95% CI: 0.92-2.24).
Our data suggest that diets high in processed meats could increase the risk for developing Type 2 diabetes.
MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant ...impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory.
Recently, we developed a human MLLr leukemia model by inducing chromosomal rearrangements in CD34+ cells using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. This MLLr model authentically mimics patient leukemic cells and can be used as a platform for novel treatment strategies. RNA sequencing of our model revealed MYC as one of the most important key drivers to promote oncogenesis. However, in clinical trials the BRD4 inhibitor JQ-1 leading to indirect blocking of the MYC pathway shows only modest activity. We and others previously reported that epigenetic drugs targeting MAT2A or PRMT5 promote cell death in MLLr cells. Therefore, we use these drugs in combination with JQ-1 leading to augmented anti-leukemic effects. Moreover, we found activation of T, NK and iNKT cells, release of immunomodulatory cytokines and downregulation of the PD-1/PD-L1 axis upon inhibitor treatment leading to improved cytotoxicity.
In summary, the inhibition of MYC and MAT2A or PRMT5 drives robust synergistic anti-leukemic activity in MLLr leukemia. Moreover, the immune system is concomitantly activated upon combinatorial inhibitor treatment, hereby further augmenting the therapeutic efficiency.
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