Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. Those include Fetal Alcohol Spectrum Disorders (FASD) with a wide range of cognitive deficiencies including impaired motor skill development. While these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We have previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells alter gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlates with motor learning deficits in the mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a novel intervention for learning disabilities in FASD.
Excessive alcohol consumption results in significant changes in gene expression and isoforms due to altered mRNA splicing. As such, an intriguing possibility is that disturbances in alternative splicing are involved in key pathological pathways triggered by alcohol exposure. However, no resources have been available to systematically analyze this possibility at a genome-wide scale. Here, we performed RNA sequencing of human fetal cortical slices that were obtained at the late first trimester and exposed to ethanol or control medium. We report 382 events that were identified as changes affecting the ratio of splicing isoforms in the ethanol-exposed fetal human cortex. Additionally, previously unreported novel isoforms of several genes were also identified. These results provide a broad perspective on the post-transcriptional regulatory network underlying ethanol-induced pathogenesis in the developing human cortex.
Background: Complicated malaria caused by Plasmodium falciparum alone or with P. vivax can lead to multi organ dysfunction. There is a paucity of studies about hepatic dysfunction in children with complicated malaria. Hence, this retrospective study was done to find out the clinico-biochemical profile of children with complicated malarial hepatic dysfunction from a malaria endemic region of India. Further, liver function test (LFT) response to Artemisinin-based combination therapy (ACT) i.e. artesunate + sulfadoxine-pyrimethamine therapy in the malarial hepatic dysfunction children was assessed. Methods: Out of 203 children confirmed to have malaria, 60 children were found to have complicated malaria with jaundice as per WHO malaria guidelines (total serum bilirubin >3 mg%). Physical examination, malaria related biochemical and ultra-sonographic findings were noted. All the children were found to be uniformly on ACT as per institute protocol adapted from WHO guidelines. Biochemical parameters of hepatic function were compared between day 1 and 4. Results: Presentations were fever, pallor and clinical jaundice in 100%, reddish urine in 63.3%, tender hepatomegaly in 100% and splenomegaly in 81.7% of the study population. Liver function test showed mild to moderate elevation of serum bilirubin and enzymes with remarkable recovery noticed with the use of ACT in all the study subjects. Conclusions: Clinical presentations of malarial hepatic dysfunction although mimics viral hepatitis, LFT showed mild to moderate elevation only. Further, ACT therapy was found effective in the management of all children with hepatic dysfunction in complicated malaria.
This study demonstrates the protective effect of 670 nm LED pre exposure on cellular enzymes against fluorescent light induced change.
Fetal alcohol spectrum disorders (FASD) show various behavioral problems due to prenatal alcohol exposure (PAE). Our previous study found significant changes in gene expressions linked to fatty acid metabolism in the brain of the PAE mouse model. Given the importance of fatty acids in normal brain functions and the contributions to neurodegenerative diseases, we hypothesized that the fatty acids changed by PAE contribute to neurobehavioral deficits in FASD. This study found an increase of palmitic acid and arachidonic acid in phospholipid compositions in the cerebral cortex of PAE at postnatal day 30. The increase of palmitic acid was consistent with the increase of the producing enzyme, fatty acid synthase (Fasn). The decrease of 26:6 fatty acid was also found in phospholipid. It is consistent with the increase of the Elongation of very long chain fatty acids protein 4 (ELOVL4) which uses 26:6 as a substrate for making very long chain fatty acids. However, there was no increase in the elongated products. Rather, we found an accumulation of the lipid droplets (LDs) in the PAE brain, suggesting changes in fatty acid metabolism that lead to the accumulation of excessive fatty acids. Although metabolic measurements, including plasma triglyceride level, were not affected by PAE, the abundance of fatty acid-related gut microbiota was altered. Interestingly, multi-omics association analysis revealed a potential contribution of the altered gut microbiota, primarily Ruminococcaceae that produces short chain fatty acid, to LD formation in the PAE brain and the behavioral problems, suggesting that the gut microbiome could serve as a tool to facilitate uncovering the brain pathophysiology of FASD and a potential target to mitigate neurobehavioral problems.
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