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Whether direct manipulation of Parkinson's disease (PD) risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue. Here, we used an adeno-associated virus serotype 9 (AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras (SNs) of two monkey groups an old group and a middle-aged group. After the operation, the old group exhibited all the classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by key pathological hallmarks of PD, such as severe nigral dopaminergic neuron loss (>64%) and evident α-synuclein pathology in the gene-edited SN. In contrast, the phenotype of their middle-aged counterparts, which also showed clear PD symptoms and pathological hallmarks, were less severe. In addition to the higher final total PD scores and more severe pathological changes, the old group were also more susceptible to gene editing by showing a faster process of PD progression. These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys. Taken together, this system can effectively develop a large number of genetically-edited PD monkeys in a short time (6-10 months), and thus provides a practical transgenic monkey model for future PD studies.
SARS-CoV-2 is a newly emerged human coronavirus that severely affected human health and the economy. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target to stop virus replication. The adenosine derivative, remdesivir, was authorized for emergency use 10 months ago by the United States FDA against COVID-19 despite its doubtful efficacy against SARS-CoV-2.
A dozen modifications based on remdesivir are tested against SARS-CoV-2 RdRp using combined molecular docking and dynamics simulation in this work.
The results reveal a better binding affinity of 11 modifications compared to remdesivir. Compounds 8, 9, 10, and 11 show the best binding affinities against SARS-CoV-2 RdRp conformations gathered during 100ns of the Molecular Dynamics Simulation (MDS) run (-8.13 ± 0.45kcal/mol, -8.09 ± 0.67kcal/mol, -8.09 ± 0.64kcal/mol, and -8.07 ± 0.73kcal/mol, respectively).
The present study suggests these four compounds as potential SARS-CoV-2 RdRp inhibitors, which need to be validated experimentally.
The present study suggests these four compounds as potential SARS-CoV-2 RdRp inhibitors, which need to be validated experimentally.Schistosomiasis causes significant morbidity and mortality. Vaccine efforts to date indicate the need to increase the immunogenicity of Schistosoma antigens. The multiple antigen-presenting system, whereby proteins are genetically fused to rhizavidin and affinity linked to biotinylated templates, enables the generation of robust immune responses. The objective of this work was to express and purify the S. mansoni antigens, SmTSP-2 and SmCD59.2, in fusion with rhizavidin. The fusion with rhizavidin greatly decreased the expression level of rSmTSP-2, but not rSmCD59.2, and both were expressed in the insoluble fraction, requiring optimization of culture conditions. Evaluation of different E. coli strains and media showed that BL21-DE3 cultured in Terrific Broth provided the highest expression levels of both proteins. Investigation of a range of time and temperature of induction showed that E. coli strains expressing rRzvSmTSP-2 and rRzvSmCD59.2 showed the highest protein production at 23 °C for 15 h. Recombinant proteins were purified by a single step of affinity chromatography allowing isolation of these proteins in high concentration and purity. The optimization process increased final soluble protein yield of rRzvSmTSP-2 by fourfold and rRzvSmCD59.2 by tenfold, providing ~ 20 mg/L of each protein. Optimized fusion protein production will allow antigen use in biotin-rhizavidin affinity platforms.Numerous studies have reported that epilepsy causes memory deficits. The present study was aimed at studying the effect of rapamycin against the memory deficiency of the pentylenetetrazole (PTZ)-kindled animal model of epilepsy. In the present experiment, we randomly chose thirty male rats from the species of Wistar and categorized them in groups of control and experiment (6 for each group). The groups of experiment received the injection of rapamycin (0.5, 1 and 2 mg/kg) intraperitoneally (i.p.) and the group of control received normal saline (0.9%) treatment. Through the PTZ's sub-threshold dose (35 mg kg-1, i.p.), all groups were kindled 12 times. Passive avoidance test (PAT) was used for gauging the memory function and the seizure behaviors after the kindling procedure. The rodents were sacrificed at the end of the trial and their brains were scooped for measuring the expression of Gabra1 and Pras40 genes. Statistical analysis unveiled that rapamycin delayed the kindling development and the onset of seizures which are tonic-clonic. Moreover, the administration of rapamycin significantly prevented memory dysfunction in epileptic rats. Finally, it was shown that rapamycin resulted in an increase in the expression levels of Gabra1 and Pras40 genes at the brain tissues. The current research design indicated that rapamycin has beneficial effects for the prevention of memory impairment against PTZ-kindling epilepsy in rats. Such promising outcomes could be attributed to its impact on the Gabra1 and Pras40 genes.Recent findings suggest a significant role of the brain-derived neurotrophic factor (BDNF) as a mediator of brain regeneration following a stab injury in zebrafish. Since BDNF has been implicated in many physiological processes, we hypothesized that these processes are affected by brain injury in zebrafish. Hence, we examined the impact of stab injury on oxidative stress and apoptosis in the adult zebrafish brain. Stab wound injury (SWI) was induced in the right telencephalic hemisphere of the adult zebrafish brain and examined at different time points. The biochemical variables of oxidative stress insult and transcript levels of antioxidant genes were assessed to reflect upon the oxidative stress levels in the brain. Immunohistochemistry was performed to detect the levels of early apoptotic marker protein cleaved caspase-3, and the transcript levels of pro-apoptotic and anti-apoptotic genes were examined to determine the effect of SWI on apoptosis. The activity of antioxidant enzymes, the level of lipid peroxidation (LPO) and reduced glutathione (GSH) were significantly increased in the injured fish brain. SWI also enhanced the expression of cleaved caspase-3 protein and apoptosis-related gene transcripts. Our results indicate induction of oxidative stress and apoptosis in the telencephalon of adult zebrafish brain by SWI. These findings contribute to the overall understanding of the pathophysiology of traumatic brain injury and adult neurogenesis in the zebrafish model and raise new questions about the compensatory physiological mechanisms in response to traumatic brain injury in the adult zebrafish brain.There is a lack of evidence on the effects of high-intensity interval training (HIIT) microcycle duration on the antioxidant capacity and hippocampal inflammatory response of young (immature) samples. This study compared two HIIT microcycles lengths on adaptation to training, antioxidant balance, and systemic and hippocampal inflammation in immature rats. Twenty-four immature Wistar rats (27 days) were equally divided into groups control; 4-day HIIT (3 training days + 1 rest day); and 7-day HIIT (6 training days + 1 rest day). Both microcycles of 4 and 7 days were 28 days of training (37-38 m min-1). Running performance improved in all training groups compared to controls (P less then 0.05). However, the 7-day HIIT group statistically increased serum interleukin-6 (IL-6) compared to the control and 4-day HIIT groups (P less then 0.05). The total serum antioxidant capacity in the 7-day HIIT group was statistically lower than in the control group (P less then 0.05). There was no statistical difference for the analysis of serum malondialdehyde between the groups. The hippocampal gene expression of IL-6, IL-1β, IL-10, and tumor necrosis factor-alpha in the training groups was statistically higher than in the control group (P = 0.01), with no significant difference between the 4-day HIIT and 7-day HIIT groups. We concluded that HIIT microcycles with a longer duration decrease the antioxidant capacity and increase the systematic and hippocampal inflammation. Thus, we suggest using short HIIT microcycles for young (immature) groups due to improved running performance with less inflammatory and antioxidant changes.
To provide a precise summary and collate the hitherto available clinical evidence on theeffect of vitamin D supplementation on clinical outcomes in COVID-19 patients.
PubMed/MEDLINE, Scopus, and Web of Science databases were systematically searched using appropriate keywords till June 8, 2021, to identify observational studies and randomized controlled trials (RCTs) reporting adverse clinical outcomes (ICU admission and/or mortality) in COVID-19 patients receiving vitamin D supplementation vs. those not receiving the same. Both prior use and use of vitamin D after COVID-19 diagnosis were considered. Unadjusted/adjusted pooled odds ratio (OR) with 95% confidence intervals (CI) were calculated (PROSPERO registration number CRD42021248488).
We identified 13 studies (10 observational, 3 RCTs) pooling data retrieved from 2933 COVID-19 patients. Pooled analysis of unadjusted data showed that vitamin D use in COVID-19 was significantly associated with reduced ICU admission/mortality (OR 0.41, 95% CI 0.20, 0.81search.
Despite the well-established benefits of exercise, pregnant women are discouraged from physical activity in hot/humid conditions to avoid hyperthermia (core temperature (T
) ≥ 39.0°C). Recent epidemiological evidence also demonstrates greater risk of negative birth outcomes following heat exposure during pregnancy, possibly due to thermoregulatory impairments. We aimed to determine (1) the risk of pregnant women exceeding a T
of 39.0°C during moderate-intensity exercise in the heat; and (2) if any thermoregulatory impairments are evident in pregnant (P) versus non-pregnant (NP) women.
Thirty participants (15 pregnant in their second trimester or third trimester) completed two separate exercise-heat exposures in a climate chamber (32°C, 45%RH). On separate occasions, each participant cycled on a semi-recumbent cycle ergometer for 45min at a workload representative of a moderate-intensity (1) non-weight-bearing (NON-WB), or (2) weight-bearing (WB) activity. Thermoregulatory responses were monitored throuatory impairments with pregnancy were observed.As the most developed city circle in northern China, allocating CO2 emission quotas at the Bohai Rim Economic Circle (BREC) city level is essential for developing specific abatement policies. Thus, with reflecting multi-principles (fairness, efficiency, sustainability, and feasibility), this paper formulates the CO2 emission quota allocation among cities in BREC in 2030 based on the multi-objective decision approach. selleck chemicals We first propose three allocation schemes based on the principles of fairness, efficiency, and sustainability, which are conducted by entropy method, zero-sum gains data envelopment (ZSG-DEA) model, and CO2 sequestration share method, respectively. Then, the CO2 allocation satisfaction is defined and used to measure the feasibility principle which is integrated as the objective function of the multi-objective decision model together with three allocation schemes to obtain the optimal allocation results. The results show that Beijing, Tianjin, Dalian, Shijiazhuang, Yantai, Weifang, and Linyi enjoy the largest CO2 emission quotas, having 1179.
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