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Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder marked by functional abnormalities in brain that causes social and linguistic difficulties. The incidence of ASD is more prevalent in males compared to females, but the underlying mechanism, as well as molecular indications for identifying sex-specific differences in ASD symptoms remain unknown. Thus, impacting the development of personalized strategy towards pharmacotherapy of ASD. The current study employs an integrated bioinformatic approach to investigate the genes and pathways uniquely associated with sex specific differences in autistic individuals. Based on microarray dataset (GSE6575) extracted from the gene expression omnibus, the dysregulated genes between the autistic and the neurotypical individuals for both sexes were identified. Gene set enrichment analysis was performed to ascertain biological activities linked to the dysregulated genes. Protein–protein interaction network analysis was carried out to identify hub genes. The identified hub genes were examined to determine their functions and involvement in the associated pathways using Enrichr. Additionally, hub genes were validated from autism-associated databases and the potential small molecules targeting the hub genes were identified. The present study utilized whole blood transcriptomic gene expression analysis data and identified 2211 and 958 differentially expressed unique genes in males and females respectively. The functional enrichment analysis revealed that male hub genes were functionally associated with RNA polymerase II mediated transcriptional regulation whereas female hub genes were involved in intracellular signal transduction and cell migration. The top male hub genes exhibited functional enrichment in tyrosine kinase signalling pathway. The pathway enrichment analysis of male hub genes indicates the enrichment of papillomavirus infection. Female hub genes were enriched in androgen receptor signalling pathway and functionally enriched in focal adhesion specific excision repair. Identified drug like candidates targeting these genes may serve as a potential sex specific therapeutics. Wortmannin for males, 5-Fluorouracil for females had the highest scores. Targeted and sex-specific pharmacotherapies may be created for the management of ASD. The current investigation identifies sex-specific molecular signatures derived from whole blood which may serve as a potential peripheral sex-specific biomarkers for ASD. The study also uncovers the possible pharmacological interventions against the selected genes/pathway, providing support in development of therapeutic strategies to mitigate ASD. However, experimental proofs on biological systems are warranted. [ABSTRACT FROM AUTHOR]

This article constructs examples of associative submanifolds in G 2 –manifolds obtained by resolving G 2 –orbifolds using Joyce's generalised Kummer construction. As the G 2 –manifolds approach the G 2 –orbifolds, the volume of the associative submanifolds tends to zero. This partially verifies a prediction due to Halverson and Morrison. [ABSTRACT FROM AUTHOR]

We study a flow of G 2 -structures that all induce the same Riemannian metric. This isometric flow is the negative gradient flow of an energy functional. We prove Shi-type estimates for the torsion tensor T along the flow. We show that at a finite-time singularity the torsion must blow up, so the flow will exist as long as the torsion remains bounded. We prove a Cheeger–Gromov type compactness theorem for the flow. We describe an Uhlenbeck-type trick which together with a modification of the underlying connection yields a nice reaction–diffusion equation for the torsion along the flow. We define a scale-invariant quantity Θ for any solution of the flow and prove that it is almost monotonic along the flow. Inspired by the work of Colding–Minicozzi (Ann Math (2) 175(2):755–833, 2012) on the mean curvature flow, we define an entropy functional and after proving an ε -regularity theorem, we show that low entropy initial data lead to solutions of the flow that exist for all time and converge smoothly to a G 2 -structure with divergence-free torsion. We also study finite-time singularities and show that at the singular time the flow converges to a smooth G 2 -structure outside a closed set of finite 5-dimensional Hausdorff measure. Finally, we prove that if the singularity is of Type- I then a sequence of blow-ups of a solution admits a subsequence that converges to a shrinking soliton for the flow. [ABSTRACT FROM AUTHOR]

Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade. [ABSTRACT FROM AUTHOR]

Mounting evidence suggests that long-term aluminum exposure results in severe toxic effects, including neurobehavioral and neurochemical anomalies. The present study was performed to examine the neuroprotective potential of hesperidin and silibinin against aluminum chloride (AlCl)-induced neurotoxicity in mice. AlCl (100 mg/kg/day) was injected daily through oral gavage for 42 days. Concomitantly, hesperidin (50 and 100 mg/kg/day, p.o.) and silibinin (100 and 200 mg/kg/day, p.o.) was administered for 42 days in different groups. The extent of cognitive impairment was assessed by Morris water maze and novel object recognition test on the 43rd day. Neurotoxicity was assessed by measuring oxido-nitrosative stress and proinflammatory cytokines in the hippocampus of mice. Six weeks treatment with AlCl caused cognitive impairment as indicated by an increase in the retention latency time and reduction in the percentage of recognition index. AlCl-treated group showed oxido-nitrosative stress as indicated by increase in the level of lipid peroxidation, nitrite and depleted reduced glutathione, catalase activity in the hippocampus. Moreover, the chronic AlCl administration raised the proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α) level and increased acetylcholinesterase activity and reduced the BDNF content in the hippocampus of AlCl-treated animals. However, chronic treatment with hesperidin and silibinin at higher doses significantly ameliorated the AlCl-induced cognitive impairment and hippocampal biochemical anomalies. The present study clearly indicated that hesperidin and silibinin exert neuroprotective effects against AlCl-induced cognitive impairment and neurochemical changes. Amelioration of cognitive impairment may be attributed to the impediment of oxido-nitrosative stress and inflammation in the hippocampus. [ABSTRACT FROM AUTHOR]