Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid  and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2-to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation.
Edited by Dennis R. VoelkerA chronic high fat diet results in hepatic mitochondrial dysfunction and induction of peroxisomal fatty acid oxidation (FAO); whether specific inhibition of peroxisomal FAO benefits mitochondrial FAO and reactive oxygen species (ROS) metabolism remains unclear. In this study a specific inhibitor for the rate-limiting enzyme involved in peroxisomal FAO, acyl-CoA oxidase-1 (ACOX1) was developed and used for the investigation of peroxisomal FAO inhibition upon mitochondrial FAO and ROS metabolism. Specific inhibition of ACOX1 by 10,12-tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5-monophosphateactivated protein kinase) pathway and proliferator activator receptor ␣ and reduced hydrogen peroxide accumulation in high fat diet-fed rats, which significantly decreased hepatic lipid and ROS contents, reduced body weight gain, and decreased serum triglyceride and insulin levels. Inhibition of ACOX1 is a novel and effective approach for the treatment of high fat dietor obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism. Hepatic lipid and reactive oxygen species (ROS)2 accumulation due to hyperlipidemia and obesity are critical factors associated with the prevalence of metabolic and cardiovascular diseases (1, 2). Decreased mitochondrial fatty acid oxidation (FAO) and increased lipogenesis are major contributors to lipid accumulation in liver and other tissues (3). Excessive hepatic ROS generation and decreased cellular antioxidative activity lead to oxidative stress and hepatic oxidative injury (2, 4). Agents that are able to promote mitochondrial fatty acid oxidation or have antilipogenic and antioxidative effects will improve lipid and ROS metabolism and attenuate hepatic steatosis and oxidative injury.Peroxisomes are subcellular respiratory organelles that are critical for the metabolism of long chain and branched-chain fatty acids (5). Peroxisomes are sensitive to external signals and are easy to proliferate under conditions of high fat diet (HFD) (6, 7), diabetes (8), or hypolipidemic drug treatment (9); peroxisomal FAO is induced, oxidation capacity is increased by 2-10-fold, and peroxisomal FAO is regulated by the peroxisome proliferator activator receptor ␣ isoform (PPAR␣) (5).Acyl-CoA oxidase-1 (ACOX1, EC 1.3.3.6) is a flavoenzyme that catalyzes the initial and rate-determining reaction of the classical peroxisomal FAO using straight-chain fatty acyl-CoAs as the substrates, which donates electrons to molecular oxygen generating hydrogen peroxide; this byproduct is further decomposed by catalase, as shown in Fig. 1. The classical peroxisomal FAO has been known for nearly 40 years (9), but it is still not clear about the exact role of peroxisomal FAO in cellular fatty acid metabolism and especially its effect on mitochondrial fatty acid oxidation. Several lines of evidence have shown that chronic induction of peroxisomal FAO may cause oxidative stress and is potentially detrimental to mitochondrial fa...
Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking β-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial β-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.
Since the discovery that honey bee viruses play a role in colony decline, researchers have made major breakthroughs in understanding viral pathology and infection processes in honey bees. Work on virus transmission patterns and virus vectors, such as the mite Varroa destructor, has prompted intense efforts to manage honey bee health. However, little is known about the occurrence of honey bee viruses in bee predators, such as vespids. In this study, we characterized the occurrence of 11 honey bee viruses in five vespid species and one wasp from four provinces in China and two vespid species from four locations in France. The results showed that all the species from China carried certain honey bee viruses, notably Apis mellifera filamentous virus (AmFV), Deformed wing virus (DWV), and Israeli acute paralysis virus (IAPV); furthermore, in some vespid colonies, more than three different viruses were identified. In France, DWV was the most common virus; Sacbrood virus (SBV) and Black queen cell virus (BQCV) were observed in one and two samples, respectively. Phylogenetic analyses of IAPV and BQCV sequences indicated that most of the IAPV sequences belonged to a single group, while the BQCV sequences belonged to several groups. Additionally, our study is the first to detect Lake Sinai virus (LSV) in a hornet from China. Our findings can guide further research into the origin and transmission of honey bee viruses in Vespidae, a taxon of ecological, and potentially epidemiological, relevance.
By providing pollination services, bees are among the most important insects, both in ecological and economical terms. Combined next-generation and classical sequencing approaches were applied to discover and study new insect viruses potentially harmful to bees. A bioinformatics virus discovery pipeline was used on individual Illumina transcriptomes of 13 wild bees from three species from the genus Halictus and 30 ants from six species of the genera Messor and Aphaenogaster. This allowed the discovery and description of three sequences of a new virus termed Halictus scabiosae Adlikon virus (HsAV). Phylogenetic analyses of ORF1, RNA-dependent RNA-polymerase (RdRp) and capsid genes showed that HsAV is closely related to (+)ssRNA viruses of the unassigned Sinaivirus genus but distant enough to belong to a different new genus we called Halictivirus. In addition, our study of ant transcriptomes revealed the first four sinaivirus sequences from ants (Messor barbarus, M. capitatus and M. concolor). Maximum likelihood phylogenetic analyses were performed on a 594 nt fragment of the ORF1/RdRp region from 84 sinaivirus sequences, including 31 new Lake Sinai viruses (LSVs) from honey bees collected in five countries across the globe and the four ant viral sequences. The phylogeny revealed four main clades potentially representing different viral species infecting honey bees. Moreover, the ant viruses belonged to the LSV4 clade, suggesting a possible cross-species transmission between bees and ants. Lastly, wide honey bee screening showed that all four LSV clades have worldwide distributions with no obvious geographical segregation.
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