Genome-Wide Analysis of Methylome in the Mouse Brain using Long-Read Sequencing Technology

DNA methylation is an epigenetic modification that transfers a methyl group onto the C-5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA, especially in regulation of Allele Specific Expression (ASE). In this study, we used Oxford Nanopore long-read sequencing technology to profile methylome in the two inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2). Compared with bisulfite conversion followed by Illumina Sequencing, long-read sequencing technology allows us to achieve much longer read length of 4,653.675 base pairs on average while maintaining an average percent identity of 90.775%. We detected millions of methylation events and 1,465 differentially methylated regions (DMRs) between B6 and D2. Understanding more about how DNA methylation patterns of these mice affect neurological phenotype will further research into drug development for neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This work was conducted in the UND Department of Biology under the advisement of Dr. Xusheng Wang and supported by The UND Center for Biomedical Research Excellence (CoBRE) for Epigenomics of Development and Disease (X.W.), the UND CoBRE for Host-Pathogen Interactions (HPI) (X.W.), the ND EPSCoR STEM program (X.W.), the UND Vice President for Research & Economic Development (VPRED) seed program (X.W.), the American Society for Pharmacology & Experimental Therapeutics (ASPET) SURF Program, the Chair of the Department of Biomedical Sciences, the Division of Research & Economic Development at the University of North Dakota , an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103442, the Dean of the University of North Dakota School of Medicine & Health Sciences. A special thanks to all my peers in the Xusheng Wang Laboratory: He Huang, Ling Li, Kincaid Rowbotham, Alyssa Erickson, and the UND Genomics Core for performing the DNA extraction and sequencing.https://commons.und.edu/as-showcase/1008/thumbnail.jp

Antioxidant compounds from marine seaweeds and their mechanism of action

Investigation of natural products has moved toward marine environments as they are a source of many biologically active agents. The natural antioxidant compounds isolated from seaweeds provide a valuable contribution to the innovation of new drugs for chronic diseases associated with oxidative stress. While the antioxidant activity and nutritional benefits of various seaweed products are well recognized, their proper utilization as antioxidants remains at initial stages that require further investigative studies. This review provides a detailed study of isolated antioxidant compounds from seaweeds and their major mechanism of action by focusing on the reports from 2015 to 2019. The report discusses various active antioxidant compounds, including phenolics (e.g., phlorotannins), polysaccharides, and pigments with proven benefits against oxidative stress-related diseases, especially carotenoids, from the aspect of benefits to human health

Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy.

Microglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippocampal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention

CD40 Signaling Is Impaired in L. major–infected Macrophages and Is Rescued by a p38MAPK Activator Establishing a Host-protective Memory T Cell Response

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-γ, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major–infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major–infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance

Attenuation of in vitro host-pathogen interactions in quinolone-resistant Salmonella Typhi mutants

Objectives The relationship between quinolone resistance acquisition and invasion impairment has been studied in some Salmonella enterica serovars. However, little information has been reported regarding the invasive human-restricted pathogen Salmonella Typhi. The aim of this study was to investigate the molecular mechanisms of quinolone resistance acquisition and its impact on virulence in this serovar. Methods Two antibiotic-resistant mutants (Ty_c1 and Ty_c2) were generated from a Salmonella Typhi clinical isolate (Ty_wt). The three strains were compared in terms of antimicrobial susceptibility, molecular mechanisms of resistance, gene expression of virulence-related factors, ability to invade eukaryotic cells (human epithelial cells and macrophages) and cytokine production. Results Multidrug resistance in Ty_c2 was attributed to AcrAB/TolC overproduction, decreased OmpF (both mediated by the mar regulon) and decreased OmpC. The two mutants showed a gradually reduced expression of virulence-related genes (invA, hilA, hilD, fliC and fimA), correlating with decreased motility, reduced infection of HeLa cells and impaired uptake by and intracellular survival in human macrophages. Moreover, Ty_c2 also showed reduced tviA expression. Additionally, we revealed a significant reduction in TNF-α and IL-1β production and decreased NF-κB activation. Conclusions In this study, we provide an in-depth characterization of the molecular mechanisms of antibiotic resistance in the Salmonella Typhi serovar and evidence that acquisition of antimicrobial resistance is concomitantly detected with a loss of virulence (epithelial cell invasion, macrophage phagocytosis and cytokine production). We suggest that the low prevalence of clinical isolates of Salmonella Typhi highly resistant to ciprofloxacin is due to poor immunogenicity and impaired dissemination ability of these isolates

Dialect Accent Features for Establishing Speaker Identity

Dialect Accent Features for Establishing Speaker Identity: A Case Study discusses the subject of forensic voice identification and speaker profiling. Specifically focusing on speaker profiling and using dialects of the Hindi language, widely used in India, the authors have contributed to the body of research on speaker identification by using accent feature as the discriminating factor. This case study contributes to the understanding of the speaker identification process in a situation where unknown speech samples are in different language/dialect than the recording of a suspect. The authors' data establishes that vowel quality, quantity, intonation and tone of a speaker as compared to Khariboli (standard Hindi) could be the potential features for identification of dialect accent

Dialect Accent Features for Establishing Speaker Identity: A Case Study

Dialect Accent Features for Establishing Speaker Identity: A Case Study discusses the subject of forensic voice identification and speaker profiling. Specifically focusing on speaker profiling and using dialects of the Hindi language, widely used in India, the authors have contributed to the body of research on speaker identification by using accent feature as the discriminating factor. This case study contributes to the understanding of the speaker identification process in a situation where unknown speech samples are in different language/dialect than the recording of a suspect. The authors' data establishes that vowel quality, quantity, intonation and tone of a speaker as compared to Khariboli (standard Hindi) could be the potential features for identification of dialect accent

Dialect Accent Features for Establishing Speaker IdentityA Case Study /

XII, 60 p.online resource

Promoting autophagy to mitigate coronavirus disease pathology in the elderly

Abstract In this commentary, we highlight autophagy's important function, while identifying potential therapeutic targets for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in the elderly. Autophagy's decline in the elderly causes increased cell senescence and a dysregulated immune system. As this demographic often faces decreased vaccine‐provided immunity, coronavirus disease 2019 treatments must be developed. We discuss a recent study by Acharya et al. (2022) that found that SF2523 induced autophagy, reducing SARS‐CoV‐2 replication. Furthermore, across varying dosages, SF2523 was shown to have a synergistic effect with remdesivir or MU‐UNMC. Consequently, we believe that SF2523, alone or with other anti‐virals, is a promising potential therapeutic for preventing SARS‐CoV‐2‐related mortalities