Serum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30x10−7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction (MI) and Alzheimer’s disease (ad) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to non-alcoholic steatohepatitis (NASH); however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and ad at the exome level in the largest analysis to date.

Thalidomides were initially thought to be broad-range drugs specifically for curing insomnia and relieving morning sickness in pregnant women. However, its use was discontinued because of a major drawback of causing teratogenicity. In this study, we found that a thalidomide derivative, 5-hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33), inhibited the proliferation of MCF-7 with a half-maximal inhibitory concentration of 4.5 ± 0.4 μM. 5HPP-33 depolymerized microtubules and inhibited the reassembly of cold-depolymerized microtubules in MCF-7 cells. Using time-lapse imaging, the effect of 5HPP-33 on the dynamics of individual microtubules in live MCF-7 cells was analyzed. 5HPP-33 (5 μM) decreased the rates of growth and shortening excursions by 34 and 33%, respectively, and increased the time microtubules spent in the pause state by 92% as compared to that of the vehicle-treated MCF-7 cells. 5HPP-33 (5 μM) reduced the dynamicity of microtubules by 62% compared to the control. 5HPP-33 treatment reduced the distance between the two poles of a bipolar spindle, induced multipolarity in some of the treated cells, and blocked cells at mitosis. In vitro, 5HPP-33 bound to tubulin with a weak affinity. Vinblastine inhibited the binding of 5HPP-33 to tubulin, and 5HPP-33 inhibited the binding of BODIPY FL-vinblastine to tubulin. Further, a molecular docking analysis suggested that 5HPP-33 shares its binding site on tubulin with vinblastine. The results provided significant insight into the antimitotic mechanism of action of 5HPP-33 and also suggest a possible mechanism for the teratogenicity of thalidomides.

After decades of research on memory formation and retention, we are still searching for the definite concept and process behind neuroplasticity. This review article will address the relationship between synapses, memory formation, and memory retention and their genetic correlations. In the last six decades, there have been enormous improvements in the neurochemistry domain, especially in the area of neural plasticity. In the central nervous system, the complexity of the synapses between neurons allows communication among them. It is believed that each time certain types of sensory signals pass through sequences of synapses, these synapses can transmit the same signals more efficiently the following time. The concept of Hebb synapse has provided revolutionary thinking about the nature of neural mechanisms of learning and memory formation. To improve the local circuitry for memory formation and behavioral change and stabilization in the mammalian central nervous system, long-term potentiation and long-term depression are the crucial components of Hebbian plasticity. In this review, we will be discussing the role of glutamatergic synapses, engram cells, cytokines, neuropeptides, neurosteroids and many aspects, covering the synaptic basis of memory. Lastly, we have tried to cover the etiology of neurodegenerative disorders due to synaptic dysfunction. To enhance pharmacological interventions for neurodegenerative diseases, we need more research in this direction. With the help of technology, and a better understanding of the disease etiology, not only can we identify the missing pieces of synaptic functions, but we might also cure or even prevent serious neurodegenerative diseases like Alzheimer’s disease (AD).

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low‐density lipoprotein cholesterol (LDL), and reduced high‐density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome‐wide association studies (GWAS)–ranked genes and gene‐set enrichment analysis to identify pathways that affect serum lipids and NAFLD. We identified credible genes in these pathways and characterized missense variants in these for effects on serum traits. We used MAGENTA to identify 58 enriched pathways from publicly available TG, LDL, and HDL GWAS (n = 99,000). Three of these pathways were also enriched for associations with European‐ancestry NAFLD GWAS (n = 7176). One pathway, farnesoid X receptor (FXR)/retinoid X receptor (RXR) activation, was replicated for association in an African‐ancestry NAFLD GWAS (n = 3214) and plays a role in serum lipids and NAFLD. Credible genes (proteins) in FXR/RXR activation include those associated with cholesterol/bile/bilirubin transport/absorption (ABCC2 (MRP2) [ATP binding cassette subfamily C member (multidrug resistance‐associated protein 2)], ABCG5, ABCG8 [ATP‐binding cassette (ABC) transporters G5 and G8], APOB (APOB) [apolipoprotein B], FABP6 (ILBP) [fatty acid binding protein 6 (ileal lipid‐binding protein)], MTTP (MTP) [microsomal triglyceride transfer protein], SLC4A2 (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone–mediated control of metabolism (NR0B2 (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4 (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1 (FOXO1A) [forkhead box O1]), or other pathways (FETUB (FETUB) [fetuin B]). Missense variants in ABCC2 (MRP2), ABCG5 (ABCG5), ABCG8 (ABCG8), APOB (APOB), MTTP (MTP), NR0B2 (SHP), NR1H4 (FXR), and PPARA (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion: Genetic variants in NR1H4 (FXR) that protect against liver steatosis increase serum LDL cholesterol while variants in other members of the family have congruent effects on these traits. Human genetic pathway enrichment analysis can help guide therapeutic development by identifying effective targets for NAFLD/serum lipid manipulation while minimizing side effects. In addition, missense variants could be used in companion diagnostics to determine their influence on drug effectiveness.

We discuss a strange case of dissociative identity disorder, also known as multiple personality disorder. This article describes the case of a 55-year-old Caucasian woman with a history of substance use disorder with seven personalities. The patient describes a couple of triggers for her condition. More research is needed to understand these triggers.

Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.

The relationship between attention-deficit/hyperactivity disorder (ADHD) and the risk of alcohol abuse is widely studied. Even though this topic has been of interest for several years, it is heavily debated. We studied various papers and conducted a systematic review using PubMed as the main source of data collection. We found that several studies put forward the concept of a positive association between alcohol abuse and ADHD symptoms, but a minority of them also showed opposing and contradictory results. We discovered that this inconsistency observed in studies could be a result of a biased approach in studies and a subjective attempt in interpretations. These biases could be studied in terms of sample size involved in the analysis, age at which studies are conducted among other statistical parameters. We believe that the deviations in the outcomes prove that the studies may be incomplete and that a standardized method of interpretation is required. Therefore, this paper recommends the need for further research to explore the connection between alcohol abuse in patients showing ADHD symptoms.