Healymidtgaard5152

Gene therapy using nucleic acids has many clinical applications for the treatment of diseases with a genetic origin as well as for the development of innovative vaccine formulations. Since nucleic acids in their free form are rapidly degraded by nucleases present in extracellular matrices, have poor pharmacokinetics and hardly pass cellular membranes, carrier systems are required. Suitable carriers that protect the nucleic acid payload against enzymatic attack, prolong circulation time after systemic administration and assist in cellular binding and internalization are needed to develop nucleic acid based drug products. Viral vectors have been investigated and are also clinically used as delivery vehicles. However, some major drawbacks are associated with their use. Therefore there has been substantial attention on the use of non-viral carrier systems based on cationic lipids and polymers. This review focuses on the properties of polymer-based nucleic acid formulations, also referred as polyplexes. Different polymeric systems are summarized, and the cellular barriers polyplexes encounter and ways to tackle these are discussed. Finally attention is given to the clinical status of non-viral nucleic acid formulations.

Individuals ailing from night eating syndrome (NES) consume more than 25% of their daily food intake during the normal sleep time, delaying their sleep or waking up in the middle of the night to eat. This study explored two experimental conditions resembling NES in Wistar rats by offering palatable food during the sleep phase, alone or combined with sleep delay. Also we explored their impact on addiction-like changes in the brain and behavior.

Experiment 1 explored the brain response after a first NES-like event; experiment 2 and 3 explored addiction-like behaviors c-Fos and FosB/ΔFosB in corticolimbic regions after 4 weeks exposition to NES-like conditions and after one week of withdrawal, respectively. For all 3 experiments 6 experimental groups were used 1. Control; 2. Restricted access (1h) to high-sugar diet (HSD) or to 3. high-fat diet (HFD); 4., Sleep delay for 4h (SD) (from ZT0-ZT4, rats using slow rotating wheels); 5. SD+HSD; 6. SD+HFD.

A first event of eating a palatable diet with or without SD was sufficient to stimulate c-Fos and ΔFosB. Along 4 weeks of exposure to the palatable diets rats exhibited escalation and binge eating, which was highest for the HFD. At this stage, SD did not influence behavioral changes nor the neuronal response. After one-week in withdrawal, rats exhibited craving and effort to obtain their palatable diet. The brains of rats previously exposed to sleep delay maintained high levels of FosB/ΔFosB in the accumbens shell and high c-Fos activation in the insular cortex.

In our experimental models of NES-like a HFD in the sleep phase and SD are risk factors to develop binge eating and addiction-like behaviors.

In our experimental models of NES-like a HFD in the sleep phase and SD are risk factors to develop binge eating and addiction-like behaviors.Tobacco smoke during gestation is associated with increased consumption of palatable foods by the offspring in humans and rats. Postpartum relapse is observed in lactating women who quit smoking during pregnancy, putting their children at risk of adverse health outcomes caused by secondhand smoke. Nicotine is transferred through milk and alters the dopaminergic reward system of adult male rats, reducing dopamine action in the nucleus accumbens (NAc) and hypothalamic arcuate nucleus. Here, we evaluated the long-term effects of nicotine-only exposure during lactation on eating behavior, anxiety, locomotion, dopaminergic system, hypothalamic leptin signaling and nicotinic receptor in the adult female rat progeny. Two days after birth (PN2), Wistar rat dams were separated into control and nicotine (Nic) groups for implantation of osmotic minipumps that released respectively saline or 6 mg/kg nicotine. Lactating dams were kept with 6 pups. After weaning (PN21; nicotine withdrawal), only the female offspring were studied. Euthanasia occurred at PN180. Nic females showed hyperphagia, preference for a high-sucrose diet, increased anxiety-like behavior, lower tyrosine hydroxylase (TH), lower dopamine transporter and higher dopamine receptor (Drd2) in NAc; lower Drd1 in prefrontal cortex and lower TH in dorsal striatum (DS). These animals showed changes that can explain their hyperphagia, such as lower leptin signaling pathway (Leprb, pJAK2, pSTAT3) and Chrna7 expression in hypothalamus. Neonatal nicotine exposure affects the brain reward system of the female progeny differently from males, mainly decreasing dopamine production in NAc and DS. Therefore, Nic females are more susceptible to develop food addiction and obesity.Due to the spread of COVID 2019, the Italian government imposed a lockdown on the national territory. Initially, citizens were required to stay at home and not to mix with others outside of their household (Phase 1); eventually, some of these restrictions were lifted (Phase 2). To investigate the impact of lockdown on emotional and binge eating, an online survey was conducted to compare measures of self-reported physical (BMI), psychological (Alexithymia), affective (anxiety, stress, and depression) and social (income, workload) state during Phase 1 and Phase 2. Data from 365 Italian residents showed that increased emotional eating was predicted by higher depression, anxiety, quality of personal relationships, and quality of life, while the increase of bingeing was predicted by higher stress. Moreover, we showed that higher alexithymia scores were associated by increased emotional eating and higher BMI scores were associated with both increased emotional eating and binge eating. Finally, we found that from Phase 1 to Phase 2 binge and emotional eating decreased. These data provide evidence of the negative effects of isolation and lockdown on emotional wellbeing, and, relatedly, on eating behaviour.Exposure to Bisphenol A (BPA) during early development particularly in- utero has been linked to a wide range of pathology. The aim of this study was to examine the relationship of BPA and its naturally occurring metabolite BPA-glucuronide (BPA-g) with sex steroid hormone levels in South African mother-child pairs. Third-trimester serum maternal samples and matching cord blood samples were analyzed for BPA, BPA-g and nine sex steroid hormones using liquid chromatography tandem mass spectrometry (LC-MS/MS). Sixty maternal and child pairs were analyzed. Rank correlation demonstrated a significant positive relationship between cord blood estradiol and cord blood BPA (p = 0.002) and maternal BPA levels (p = 0.02) respectively. Cord blood testosterone from male infants showed a negative Spearman's correlation (r=-0.5, p = 0.02) with maternal BPA-g. There was no statistical difference in total testosterone levels in cord blood from male and female infants. The findings of the current study indicate a significant relationship between some key sex steroid hormones namely testosterone, dihydrotestosterone and estradiol and fetal exposure BPA.The panel of suitable reference genes in the fetal liver have not been reported. In this study, five commonly used reference genes (GAPDH, β-actin, Rn18 s, Rpl13a, and Rps29) were firstly selected as candidates. Bestkeeper, GeNorm, and NormFinder software were then used to screen out the panel of suitable reference genes of male and female fetal rat liver under physiological and prenatal dexamethasone exposure (PDE) conditions. Finally, we verified the reliability of the screened panel of reference genes by standardizing sterol regulatory element binding protein 1c (SREBP1c) expression with different reference genes. The results showed that GAPDH + Rn18 s and GAPDH + Rpl13a were respectively the panel of suitable reference genes in male and female rat fetal liver under the physiological model, while Rn18 s + Rps29 and GAPDH + Rn18 s were respectively under the PDE model. The results showed that different reference genes affected the statistical results of SREBP1c expression, and the screened panel of suitable reference genes under the PDE model had smaller intragroup differences, when compared with other reference genes under physiological and PDE models. In conclusion, we screened and determined that the panel of suitable reference genes were GAPDH + Rn18 s and Rn18 s + Rps29 in the male rat fetal liver under physiological and PDE models, while they were GAPDH + Rpl13a and GAPDH + Rn18 s in the females, and confirmed that the selection of the panel of suitable reference genes in the fetal liver had gender differences and pathological model specificity.

To determine if trigeminal nerve electrical stimulation (TNS) would be an effective arousal treatment for loss of consciousness (LOC), we applied neuroscientific methods to investigate the role of potential brain circuit and neuropeptide pathway in regulating level of consciousness.

Consciousness behavioral analysis, Electroencephalogram (EEG) recording, Chemogenetics, Microarray analysis, Milliplex MAP rat peptide assay, Chromatin immune-precipitation (ChIP), Dual-luciferase reporter experiment, Western blot, PCR and Fluorescence in situ hybridization (FISH).

TNS can markedly activate the neuronal activities of the lateral hypothalamus (LH) and the spinal trigeminal nucleus (Sp5), as well as improve rat consciousness level and EEG activities. I138 Then we proved that LH activation and upregulated neuropeptide hypocretin are beneficial for promotion of consciousness recovery. We then applied gene microarray experiment and found hypocretin might be mediated by a well-known transcription factor Early growth response gene 1 (EGR1), and the results were confirmed by ChIP and Dual-luciferase reporter experiment.

This study illustrates that TNS is an effective arousal strategy Treatment for LOC state via the activation of Sp5 and LH neurons and upregulation of hypocretin expression.

This study illustrates that TNS is an effective arousal strategy Treatment for LOC state via the activation of Sp5 and LH neurons and upregulation of hypocretin expression.

Liver transplant priority in the US and Europe follows the 'sickest-first' principle. However, for patients with hepatocellular carcinoma (HCC), priority is based on binary tumor criteria to expedite transplant for patients with 'acceptable' post-transplant outcomes. Newer risk scores developed to overcome limitations of these binary criteria are insufficient to be used for waitlist priority as they focus solely on HCC-related pre-transplant variables. We sought to develop a risk score to predict post-transplant survival for patients using HCC- and non-HCC-related variables.

We performed a retrospective cohort study using national registry data on adult deceased-donor liver transplant (DDLT) recipients with HCC from 2/27/02-12/31/18. We fit Cox regression models focused on 5- and 10-year survival to estimate beta coefficients for a risk score using manual variable selection. We then calculated absolute predicted survival time and compared it to available risk scores.

Among 6,502 adult DDLT recipients wiansplant.

We created a risk score to predict how long patients with liver cancer will live if they get a liver transplant. In the future, this could be used to decide which waitlisted patients should get the next transplant.