An evaluation of the effectiveness of perampanel in people with epilepsy who have previously undergone resective surgery and/or implantation of a vagal nerve stimulator.

About 30% of people with epilepsy (PWE) are drug-resistant. Those with focal seizures may be suitable for epilepsy surgery. Those not amenable to resective surgery can be considered for vagus nerve stimulation (VNS). However, after operative procedures, around 50% of patients continue to experience seizures. A multi-center retrospective study assessing perampanel effectiveness and tolerability for PWE who have undergone surgical resection and/or VNS implantation was performed. The primary outcome was ≥50% reduction in seizure frequency while secondary outcomes included side effects (SEs), dose-related effectiveness, and toxicity. The median perampanel dose was 6 mg. Only one PWE became seizure free. A ≥50% decrease in seizure frequency was observed in 52.8% of the post-resection group and 16.9% of the VNS group (p < 0.001), while SEs were seen in 44.8% and 41.1%, respectively. Perampanel doses greater than 8 mg led to better response in both groups, especially in the post-VNS cohort. SEs were not dose-related and the safety profile was similar to previous observational studies. Perampanel can be beneficial in these two super-refractory epilepsy groups, particularly in PWE with seizures after surgical resection. Doses of more than 8 mg appear to be well tolerated and may be more effective than lower doses in PWE after surgical interventions.

The Role of the Mycobiome in Women's Health.

Although the human bacteriome and virome have gained a great deal of attention over the years, the human mycobiome has been far more neglected despite having significant value and implications in human health. In women, mycobiome profiles in breastmilk, vaginal regions, the gut, skin, and the oral cavity can provide insight into women's health, diseases, and microbiome dysbiosis. Analyses of mycobiome composition under factors, such as health, age, diet, weight, and drug exposure (including antibiotic therapies), help to elucidate the various roles of women's mycobiome in homeostasis, microbiome interactions (synergistic and antagonistic), and health. This review summarizes the most recent updates to mycobiome knowledge in these critical areas.

The Impact of Human Activities on Zoonotic Infection Transmissions.

As humans expand their territories across more and more regions of the planet, activities such as deforestation, urbanization, tourism, wildlife exploitation, and climate change can have drastic consequences for animal movements and animal-human interactions. These events, especially climate change, can also affect the arthropod vectors that are associated with the animals in these scenarios. As the COVID-19 pandemic and other various significant outbreaks throughout the centuries have demonstrated, when animal patterns and human interactions change, so does the exposure of humans to zoonotic pathogens potentially carried by wildlife. With approximately 60% of emerging human pathogens and around 75% of all emerging infectious diseases being categorized as zoonotic, it is of great importance to examine the impact of human activities on the prevalence and transmission of these infectious agents. A better understanding of the impact of human-related factors on zoonotic disease transmission and prevalence can help drive the preventative measures and containment policies necessary to improve public health.

INO1 induction requires chromatin remodelers Ino80p and Snf2p but not the histone acetylases.

Transcriptional co-activators contribute to gene expression through different mechanisms. We used various biochemical tools available for Saccharomyces cerevisiae to examine the mechanism of INO1 expression. INO1 encodes inositol-3-phosphate synthase, which catalyzes the rate-limiting step in the synthesis of inositol, a key player in phospholipid biosynthesis. Herein, we had demonstrated that the recruitment of histone acetylases Gcn5p and Esa1p mainly relied on the presence of transcriptional activator Ino2p during INO1 activation. However, the presence of the chromatin remodelers, Ino80p and Snf2p, may contribute to the additive effect of Gcn5p recruitment. We also showed that the recruitment of chromatin remodelers, Ino80p and Snf2p, is independent of the presence of histone acetylases. Furthermore, INO1 expression can be activated exclusively by the activator and chromatin remodelers, suggesting a dispensable role of histone acetylases in INO1 induction. Therefore, our data provide a mechanism for cross talk within transcriptional co-activators during INO1 activation.

The Use of Natural Methods to Control Foodborne Biofilms.

Biofilms are large aggregates of various species of bacteria or other microorganisms tightly attached to surfaces through an intricate extracellular matrix. These complex microbial communities present quite the challenge in the food processing industry, as conditions such as raw meats and diverse food product content in contact with workers, drains, machinery, and ventilation systems, make for prime circumstances for contamination. Adding to the challenge is the highly resistant nature of these biofilm growths and the need to keep in mind that any antimicrobials utilized in these situations risk health implications with human consumption of the products that are being processed in these locations. For that reason, the ideal means of sanitizing areas of foodborne biofilms would be natural means. Herein, we review a series of innovative natural methods of targeting foodborne biofilms, including bacteriocins, bacteriophages, fungi, phytochemicals, plant extracts, essential oils, gaseous and aqueous control, photocatalysis, enzymatic treatments, and ultrasound mechanisms.

Phylogenetic Diversity of Animal Oral and Gastrointestinal Viromes Useful in Surveillance of Zoonoses.

Great emphasis has been placed on bacterial microbiomes in human and animal systems. In recent years, advances in metagenomics have allowed for the detection and characterization of more and more native viral particles also residing in these organisms. The digestive tracts of animals and humans-from the oral cavity, to the gut, to fecal excretions-have become one such area of interest. Next-generation sequencing and bioinformatic analyses have uncovered vast phylogenetic virome diversity in companion animals, such as dogs and cats, as well as farm animals and wildlife such as bats. Zoonotic and arthropod-borne illnesses remain major causes of worldwide outbreaks, as demonstrated by the devastating COVID-19 pandemic. This highlights the increasing need to identify and study animal viromes to prevent such disastrous cross-species transmission outbreaks in the coming years. Novel viruses have been uncovered in the viromes of multiple organisms, including birds, bats, cats, and dogs. Although the exact consequences for public health have not yet become clear, many analyses have revealed viromes dominated by RNA viruses, which can be the most problematic to human health, as these genomes are known for their high mutation rates and immune system evasion capabilities. Furthermore, in the wake of worldwide disruption from the COVID-19 pandemic, it is evident that proper surveillance of viral biodiversity is crucial. For instance, gut viral metagenomic analysis in dogs has shown close relationships between the highly abundant canine coronavirus and human coronavirus strains 229E and NL63. Future studies and vigilance could potentially save many lives.

Telomeric and Sub-Telomeric Structure and Implications in Fungal Opportunistic Pathogens.

Telomeres are long non-coding regions found at the ends of eukaryotic linear chromosomes. Although they have traditionally been associated with the protection of linear DNA ends to avoid gene losses during each round of DNA replication, recent studies have demonstrated that the role of these sequences and their adjacent regions go beyond just protecting chromosomal ends. Regions nearby to telomeric sequences have now been identified as having increased variability in the form of duplications and rearrangements that result in new functional abilities and biodiversity. Furthermore, unique fungal telomeric and chromatin structures have now extended clinical capabilities and understanding of pathogenicity levels. In this review, telomere structure, as well as functional implications, will be examined in opportunistic fungal pathogens, including Aspergillus fumigatus, Candida albicans, Candida glabrata, and Pneumocystis jirovecii.

Gene-wide histone acetylation at the yeast INO1 requires the transcriptional activator Ino2p.

The relationship between histone acetylation and transcriptional activation at the yeast INO1 gene was addressed. INO1 encodes a key enzyme required for the de novo synthesis of phosphatidylinositol. Induction of INO1 resulted in acetylation of both histones H3 and H4 at the INO1 promoter and sequences farther downstream in the coding region, suggesting a gene-wide acetylation in response to transcriptional activation. Such chromatin remodeling activity requires the presence of transcriptional activator Ino2p. This indicates that histone acetylation is an activator-dependent event. Furthermore, the increase of histone acetylation is due to the increase of acetylation levels per nucleosome rather than the increase of nucleosome density. Therefore, these observations constitute evidence for the molecular mechanism of the correlation between histone acetylation and INO1 activity.

Accumulation of unacetylatable Snf2p at the INO1 promoter is detrimental to remodeler recycling supply for CUP1 induction.

Chromatin structure plays a decisive role in gene regulation through the actions of transcriptional activators, coactivators, and epigenetic machinery. These trans-acting factors contribute to gene expression through their interactions with chromatin structure. In yeast INO1 activation, transcriptional activators and coactivators have been defined through intense study but the mechanistic links within these trans-acting factors and their functional implications are not yet fully understood. In this study, we examined the crosstalk within transcriptional coactivators with regard to the implications of Snf2p acetylation during INO1 activation. Through various biochemical analysis, we demonstrated that both Snf2p and Ino80p chromatin remodelers accumulate at the INO1 promoter in the absence of Snf2p acetylation during induction. Furthermore, nucleosome density and histone acetylation patterns remained unaffected by Snf2p acetylation status. We also showed that cells experience increased sensitivity to copper toxicity when remodelers accumulate at the INO1 promoter due to the decreased CUP1 expression. Therefore, our data provide evidence for crosstalk within transcriptional co-activators during INO1 activation. In light of these findings, we propose a model in which acetylation-driven chromatin remodeler recycling allows for efficient regulation of genes that are dependent upon limited co-activators.

Epigenetic Modifications in Alzheimer's Neuropathology and Therapeutics.

Transcriptional activation is a highly synchronized process in eukaryotes that requires a series of cis- and trans-acting elements at promoter regions. Epigenetic modifications, such as chromatin remodeling, histone acetylation/deacetylation, and methylation, have frequently been studied with regard to transcriptional regulation/dysregulation. Recently however, it has been determined that implications in epigenetic modification seem to expand into various neurodegenerative disease mechanisms. Impaired learning and memory deterioration are cognitive dysfunctions often associated with a plethora of neurodegenerative diseases, including Alzheimer's disease. Through better understanding of the epigenetic mechanisms underlying these dysfunctions, new epigenomic therapeutic targets, such as histone deacetylases, are being explored. Here we review the intricate packaging of DNA in eukaryotic cells, and the various modifications in epigenetic mechanisms that are now linked to the neuropathology and the progression of Alzheimer's disease (AD), as well as potential therapeutic interventions.