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

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

Shyness and social phobia in Israeli Jewish vs Arab students

Abstract Background: Social anxiety disorder (SAD) has been repeatedly shown to be very prevalent in the Western society with prevalence rates of 10% or above. However, very few studies have been performed in the Middle East and in Arab countries. Methods: A total of 300 Israeli students participated in our study and were administered the Liebowitz Social Anxiety Scale (LSAS), the Cheek and Buss Shyness Questionnaire (CBSQ), and a sociodemographic questionnaire. Results: A total of 153 Jewish and 147 Arab students participated in the survey. Social anxiety disorder was found in 12.33% of the sample, according to the LSAS cutoff score of more than 60. The 2 subsamples had similar LSAS and CBSQ scores and similar SAD-positive rates (LSAS N60). Females had higher scores on the LSAS, as were those without a spouse and those who had been in psychological treatment. Based on a regression analysis, the significant predictors of the LSAS score were the CBSQ score and female sex. A very high correlation was found between the LSAS and the CBSQ scores. Conclusions: Although our sample is not representative of the whole Israeli population, we conclude that SAD and shyness were similarly prevalent in Jewish and Arab students in Israel. Social anxiety disorder scores were higher among females, those without a spouse, and those who received psychological treatment. Further studies on the clinical and cultural characteristics of SAD in Israeli subcultures would add to the growing body of knowledge on SAD in various cultures

Foliar Application of dsRNA Targeting Endogenous Potato (Solanum tuberosum) Isoamylase Genes ISA1, ISA2, and ISA3 Confers Transgenic Phenotype

Isoamylase (ISA) is a debranching enzyme found in many plants, which hydrolyzes (1-6)-α-D glucosidic linkages in starch, amylopectin, and β-dextrins, and is thought to be responsible for starch granule formation (ISA1 and ISA2) and degradation (ISA3). Lipid-modified PEI (lmPEI) was synthesized as a carrier for long double-stranded RNA (dsRNA, 250-bp), which targets the three isoamylase isoforms. The particles were applied to the plant via the foliar spray and were differentially effective in suppressing the expressions of ISA1 and ISA2 in the potato leaves, and ISA3 in the tubers. Plant growth was not significantly impaired, and starch levels in the tubers were not affected as well. Interestingly, the treated plants had significantly smaller starch granule sizes as well as increased sucrose content, which led to an early sprouting phenotype. We confirm the proposal of previous research that an increased number of small starch granules could be responsible for an accelerated turnover of glucan chains and, thus, the rapid synthesis of sucrose, and we propose a new relationship between ISA3 and the starch granule size. The implications of this study are in achieving a transgenic phenotype for endogenous plant genes using a systemic, novel delivery system, and foliar applications of dsRNA for agriculture

The effect of MPH on PPI.

<p>Significant differences in PPI scores were observed. EE led to the highest PPI compared with all groups (<i>P</i><0.0001). Following MPH treatment, the EES group showed higher PPI compared with control (<i>P</i><0.0001) and stress (<i>P</i><0.001) groups. A panel of representative traces demonstrate the differences in maximal response inhibition (at pre-intensity of 69 dB) of all four groups, with and without MPH. n = 9 to 10 per group.</p

The effect of MPH on locomotor activity.

<p>A significant difference in distance (A) and velocity (B) were detected between the groups in the open field test. Rats exposed to MPH following EE showed the lowest distance and velocity. These effects were not related to differences in body weight (C). MPH treatment significantly increased freezing duration (D) compared to saline. Following EE, MPH led to the highest freezing duration. * <i>P</i><0.0001 versus control; ** a: <i>P</i><0.022, b: <i>P</i><0.008, c: <i>P</i><0.0001 versus EE saline; n = 9 to 10 per group.</p