A Review of APOE Genotype-Dependent Autophagic Flux Regulation in Alzheimer’s Disease

Autophagy is a basic physiological process maintaining cell renewal, the degradation of dysfunctional organelles, and the clearance of abnormal proteins and has recently been identified as a main mechanism underlying the onset and progression of Alzheimer’s disease (AD). The APOE ɛ4 genotype is the strongest genetic determinant of AD pathogenesis and initiates autophagic flux at different times. This review synthesizes the current knowledge about the potential pathogenic effects of ApoE4 on autophagy and describes its associations with the biological hallmarks of autophagy and AD from a novel perspective. Via a remarkable variety of widely accepted signaling pathway markers, such as mTOR, TFEB, SIRT1, LC3, p62, LAMP1, LAMP2, CTSD, Rabs, and V-ATPase, ApoE isoforms differentially modulate autophagy initiation; membrane expansion, recruitment, and enclosure; autophagosome and lysosome fusion; and lysosomal degradation. Although the precise pathogenic mechanism varies for different genes and proteins, the dysregulation of autophagic flux is a key mechanism on which multiple pathogenic processes converge.

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs—including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria—could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.

The mosaic mtr locus as major genetic determinant of azithromycin resistance of Neisseria gonorrhoeae, Germany, 2018

Within the German Gonococcal Resistance Network (GORENET) Neisseria gonorrhoeae (NG) sample collection, azithromycin-resistant NG isolates increased from 4.3% in 2016 to 9.2% in 2018. We aim to understand this observed increase using whole genome sequencing of NG isolates combined with epidemiological and clinical data. Reduced susceptibility to azithromycin in 2018 was predominately clonal (NG-MAST G12302) and could mainly be accounted to the recently described mosaic-like mtr locus. Our data suggest that, together with horizontal gene transfer of resistance determinants and well-established point mutations, international spread of resistant lineages plays a major role regarding azithromycin resistance in Germany.

Selection of uric acid oxidizing-Lactobacillus plantarum isolates based on their genetic determinant and uricase kinetics

Hyperuricemia is a condition characterized by abnormally elevated levels of uric acid in the blood. It has been a leading morbidity disease. Microbial uricase can be used to oxidize uric acid into allantoin and hydrogen peroxide in the presence of oxygen and therefore has the potential to play an essential role in reducing uric acid in the people suffering from degenerative disease of hyperuricemia. The present study aims to select uric acid oxidizing-Lactobacillus plantarum isolates based on their genetic determinant and uricase kinetics. A collection of Lactobacillus plantarum isolates were grown on a selective differential medium followed by measuring their uricase activity spectrophotometrically. Specific primers for detection of uricase gene were designed. The uricase coding gene (uox) was then detected in all of the selected isolates by using a qPCR method employing the designed specific primers. The uricase kinetics was determined by the Lineweaver-Burk method. Results showed that all isolates had uricase activity and 4 potential isolates were selected based on their superior uricase activity. The uox gene was detected in all of the selected isolates. The kinetics analysis, however, revealed that only the L. plantarum K-Mar-A2 show strongest substrate affinity and was considered a potential candidate to be developed as a source of therapeutic agent for hyperuricemia.