Nanodelivery of nucleic acids

Funding: This work was supported by the European Research Council (ERC) Starting Grant (ERC-StG-2019-848325 to J. Conde) and the Fundação para a Ciência e a Tecnologia FCT Grant (PTDC/BTM-MAT/4738/2020 to J. Conde). J.S. acknowledges US National Institute of Health (NIH) grants (R01CA200900, R01HL156362 and R01HL159012), the US DoD PRCRP Idea Award with Special Focus (W81XWH1910482), the Lung Cancer Discovery Award from the American Lung Association and the Innovation Discovery Grants award from the Mass General Brigham. H.L., D.Y. and X.Z. were supported by the National Key R&D Program of China (no. 2020YFA0710700), the National Natural Science Foundation of China (nos 21991132, 52003264, 52021002 and 52033010) and the Fundamental Research Funds for the Central Universities (no. WK2060000027).There is growing need for a safe, efficient, specific and non-pathogenic means for delivery of gene therapy materials. Nanomaterials for nucleic acid delivery offer an unprecedented opportunity to overcome these drawbacks; owing to their tunability with diverse physico-chemical properties, they can readily be functionalized with any type of biomolecules/moieties for selective targeting. Nucleic acid therapeutics such as antisense DNA, mRNA, small interfering RNA (siRNA) or microRNA (miRNA) have been widely explored to modulate DNA or RNA expression Strikingly, gene therapies combined with nanoscale delivery systems have broadened the therapeutic and biomedical applications of these molecules, such as bioanalysis, gene silencing, protein replacement and vaccines. Here, we overview how to design smart nucleic acid delivery methods, which provide functionality and efficacy in the layout of molecular diagnostics and therapeutic systems. It is crucial to outline some of the general design considerations of nucleic acid delivery nanoparticles, their extraordinary properties and the structure–function relationships of these nanomaterials with biological systems and diseased cells and tissues.publishersversionpublishe

Impairment of Serine Transport Across the Blood-Brain Barrier by Deletion of Slc38a5 Causes Developmental Delay and Motor Dysfunction

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development

Environmental Enrichment Preceding Early Adulthood Methylphenidate Treatment Leads to Long Term Increase of Corticosterone and Testosterone in the Rat

Attention-deficit/hyperactivity disorder (ADD/ADHD) has been emerging as a world-wide psychiatric disorder. There appears to be an increasing rate of stimulant drug abuse, specifically methylphenidate (MPH) which is the most common treatment for ADHD, among individuals who do not meet the criteria for ADHD and particularly for cognitive enhancement among university students. However, the long term effects of exposure to MPH are unknown. Thus, in light of a developmental approach in humans, we aimed to test the effects of adolescence exposure to enriched environment (EE) followed by MPH administration during early adulthood, on reactions to stress in adulthood. Specifically, at approximate adolescence [post natal days (PND) 30–60] rats were reared in EE and were treated with MPH during early adulthood (PND 60–90). Adult (PND 90–92) rats were exposed to mild stress and starting at PND 110, the behavioral and endocrine effects of the combined drug and environmental conditions were assessed. Following adolescence EE, long term exposure to MPH led to decreased locomotor activity and increased sucrose preference. EE had a beneficial effect on PPI (attentive abilities), which was impaired by long term exposure to MPH. Finally, the interaction between EE and, exposure to MPH led to long-term elevated corticosterone and testosterone levels. In view of the marked increase in MPH consumption over the past decade, vigilance is crucial in order to prevent potential drug abuse and its long term detrimental consequences

Morphological changes in hippocampal dentate gyrus synapses following spatial learning in rats are transient

The hippocampus is believed to play a crucial role in the formation of memory for spatial tasks. In the present study quantitative electron microscopy was used to investigate morphological changes in the hippocampal dentate gyrus of 3-month-old male rats at 3, 9 and 24 h after training to find a hidden platform in a Morris water maze. Average escape latency (time taken to reach the platform) in all trained groups decreased progressively with increased training but data from a probe trial (quadrant analysis test) at the end of training indicated that only animals in the 9- and 24-h groups, not the 3-h group, displayed significant retention of platform location. Unbiased stereological methods were used to estimate synapse and neuronal density at each time point after training. The majority of synapses had unperforated postsynaptic densities, were localized on small dendritic spines and were classed as axo-spinous. In comparison to age-matched untrained rats, significant but transient increases were observed in axo-spinous synapse density and synapse-to-neuron ratio 9 h after the start of training, but not at earlier (3 h) or later (24 h) times. These changes at 9 h post-training were accompanied by transient decreases in both mean synaptic height and area of postsynaptic density. No such changes were observed in an exercise-matched control group of rats, indicating that the transient synaptic changes in the dentate gyrus are most likely to be specifically related to processes involved in memory formation for the spatial learning task

Attentional Dysfunction in Adults with Posttraumatic Stress Disorder: A Scoping Review

The research protocol of a scoping review that aims to provide an overview of the available scientific literature on attentional dysfunction in adults suffering from PTSD and identify gaps in the up-to-date literature to guide future research

Challenges in Daily Life Activities of Adults with Posttraumatic Stress Disorder: A Scoping Review

A research protocol of a scoping review that aims to provide an overview of the available scientific literature on daily life activities in adults suffering from PTSD and identify gaps in the up-to-date literature to guide future research