PEG-ylated parenteral Nanoemulsions as prospective Carriers for enhanced Brain Delivery with Diazepam as a Model Drug - Physicochemical Characterisation

Parenteral nanoemulsions are regarded as biocompatible drug delivery systems for lypophilic drugs. When it comes to delivering actives to the brain as a target site, prolonged circulation time is desirable. The objective of this study was to conduct physicochemical characterization of PEGylated nanoemulsions as prospective carriers for enhanced brain delivery, using diazepam as a model active substance for brain targeting. Nanoemulsions were prepared by high pressure homogenization method and characterized regarding droplet size, zeta potential, pH, conductivity, viscosity and in vitro release profile. PEG2000-DSPE and PEG5000-DPPE were used for PEGylation. All the formulations were autoclaved and stored at room temperature. After 2 months there were no significant changes in physicochemical parameters in autoclaved formulations which rendered them as good potential templates to incorporate drugs for brain targeted delivery

Amplification dynamics of platy-1 retrotransposons in the cebidae platyrrhine lineage

© 2019 The Author(s). Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. Platy-1 elements are Platyrrhine-specific, short interspersed elements originally discovered in the Callithrix jacchus (common marmoset) genome. To date,only themarmoset genomehas been analyzed for Platy-1 repeat content.Here,we report full-length Platy-1 insertions in other NewWorld monkey (NWM) genomes (Saimiri boliviensis, squirrel monkey; Cebus imitator, capuchin monkey; and Aotus nancymaae, owl monkey) and analyze the amplification dynamics of lineage-specific Platy-1 insertions. A relatively small number of full-length and lineage-specific Platy-1 elements were found in the squirrel, capuchin, and owl monkey genomes compared with the marmoset genome. In addition, only a few older Platy-1 subfamilies were recovered in this study, with no Platy-1 subfamilies younger than Platy-1-6. By contrast, 62 Platy-1 subfamilieswere discovered in themarmoset genome.All of the lineagespecific insertions found in the squirrel and capuchin monkeys were fixed present. However, 15%of the lineage-specific Platy-1 loci in Aotus were polymorphic for insertion presence/absence. In addition, two new Platy-1 subfamilies were identified in the owl monkey genome with low nucleotide divergences compared with their respective consensus sequences, suggesting minimal ongoing retrotransposition in the Aotus genus and no current activity in the Saimiri, Cebus, and Sapajus genera. These comparative analyses highlight the finding that the high number of Platy-1 elements discovered in themarmoset genome is an exception among NWManalyzed thus far, rather than the rule. Future studies are needed to expand upon our knowledge of Platy-1 amplification in other NWM genomes

Amplification Dynamics of Platy-1 Retrotransposons in the Cebidae Platyrrhine Lineage

Platy-1 elements are Platyrrhine-specific, short interspersed elements (SINEs) originally discovered in the Callithrix jacchus (common marmoset) genome. To date, only the marmoset genome has been analyzed for Platy-1 repeat content. Here, we report full-length Platy-1 insertions in other New World monkey (NWM) genomes (Saimiri boliviensis, squirrel monkey; Cebus imitator, capuchin monkey; and Aotus nancymaae, owl monkey) and analyze the amplification dynamics of lineage-specific Platy-1 insertions. A relatively small number of full-length and lineage-specific Platy-1 elements were found in the squirrel, capuchin, and owl monkey genomes compared to the marmoset genome. In addition, only a few older Platy-1 subfamilies were recovered in this study, with no Platy-1 subfamilies younger than Platy-1-6. By contrast, 62 Platy-1 subfamilies were discovered in the marmoset genome. All of the lineage-specific insertions found in the squirrel and capuchin monkeys were fixed present. However, ∼15% of the lineage-specific Platy-1 loci in Aotus were polymorphic for insertion presence/absence. In addition, two new Platy-1 subfamilies were identified in the owl monkey genome with low nucleotide divergences compared to their respective consensus sequences, suggesting minimal ongoing retrotransposition in Aotus genus and no current activity in the Saimiri, Cebus and Sapajus genera. These comparative analyses highlight the finding that the high number of Platy-1 elements discovered in the marmoset genome is an exception among NWM analyzed thus far, rather than the rule. Future studies are needed to expand upon our knowledge of Platy-1 amplification in other NWM genomes

Analysis of lineage-specific Alu subfamilies in the genome of the olive baboon, Papio anubis

© 2018 The Author(s). Background: Alu elements are primate-specific retroposons that mobilize using the enzymatic machinery of L1 s. The recently completed baboon genome project found that the mobilization rate of Alu elements is higher than in the genome of any other primate studied thus far. However, the Alu subfamily structure present in and specific to baboons had not been examined yet. Results: Here we report 129 Alu subfamilies that are propagating in the genome of the olive baboon, with 127 of these subfamilies being new and specific to the baboon lineage. We analyzed 233 Alu insertions in the genome of the olive baboon using locus specific polymerase chain reaction assays, covering 113 of the 129 subfamilies. The allele frequency data from these insertions show that none of the nine groups of subfamilies are nearing fixation in the lineage. Conclusions: Many subfamilies of Alu elements are actively mobilizing throughout the baboon lineage, with most being specific to the baboon lineage

Amelioration of endotoxemia by a synthetic analog of Omega-3 epoxyeicosanoids

Sepsis, a systemic inflammatory response to pathogenic factors, is a difficult to treat life-threatening condition associated with cytokine and eicosanoid storms and multi-organ damage. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic (EPA) and docosahexaenoic acid, are the precursors of potent anti-inflammatory lipid mediators, including 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the main metabolite of EPA generated by cytochrome P450 epoxygenases. Searching for novel therapeutic or preventative agents in sepsis, we tested a metabolically robust synthetic analog of 17,18-EEQ (EEQ-A) for its ability to reduce mortality, organ damage, and pro-inflammatory cytokine transcript level in a mouse model of lipopolysaccharide (LPS)-induced endotoxemia, which is closely related to sepsis. Overall survival significantly improved following preventative EEQ-A administration along with decreased transcript level of pro-inflammatory cytokines. On the other hand, the therapeutic protocol was effective in improving survival at 48 hours but insignificant at 72 hours. Histopathological analyses showed significant reductions in hemorrhagic and necrotic damage and infiltration in the liver. In vitro studies with THP-1 and U937 cells showed EEQ-A mediated repression of LPS-induced M1 polarization and enhancement of IL-4-induced M2 polarization of macrophages. Moreover, EEQ-A attenuated the LPS-induced decline of mitochondrial function in THP-1 cells, as indicated by increased basal respiration and ATP production as well as reduction of the metabolic shift to glycolysis. Taken together, these data demonstrate that EEQ-A has potent anti-inflammatory and immunomodulatory properties that may support therapeutic strategies for ameliorating the endotoxemia

MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-omics profiling

The continued emergence and spread of infectious agents is of great concern, and systems biology approaches to infectious disease research can advance our understanding of host–pathogen relationships and facilitate the development of new therapies and vaccines

Item-location binding in working memory: Is it hippocampus-dependent?

A general consensus is emerging that the hippocampus has an important and active role in the creation of new long-term memory representations of associations or bindings between elements. However, it is less clear whether this contribution can be extended to the creation of temporary bound representations in working memory, involving the retention of small numbers of items over short delays. We examined this by administering a series of recognition and recall tests of working memory for color-location binding and object-location binding to a patient with highly selective hippocampal damage (Jon), and groups of control participants. Jon achieved high levels of accuracy in all working memory tests of recognition and recall binding across retention intervals of up to 10 seconds. In contrast, Jon performed at chance on an unexpected delayed test of the same object-location binding information. These findings indicate a clear dissociation between working memory and long-term memory, with no evidence for a critical hippocampal contribution to item-location binding in working memory

Classic and recent advances in understanding amnesia

Neurological amnesia has been and remains the focus of intense study, motivated by the drive to understand typical and atypical memory function and the underlying brain basis that is involved. There is now a consensus that amnesia associated with hippocampal (and, in many cases, broader medial temporal lobe) damage results in deficits in episodic memory, delayed recall, and recollective experience. However, debate continues regarding the patterns of preservation and impairment across a range of abilities, including semantic memory and learning, delayed recognition, working memory, and imagination. This brief review highlights some of the influential and recent advances in these debates and what they may tell us about the amnesic condition and hippocampal function