Neuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) share common clinical presentations, suggesting etiologic overlap. A substantial proportion of SNP-based heritability for neuropsychiatric disorders is attributable to genetic components, and genome-wide association studies (GWASs) focusing on individual diseases have identified multiple genetic loci shared between these diseases. Here, we aimed at identifying novel genetic loci associated with individual neuropsychiatric diseases and genetic loci shared by neuropsychiatric diseases. We performed multi-trait joint analyses and meta-analysis across five neuropsychiatric disorders based on their summary statistics from the Psychiatric Genomics Consortium (PGC), and further carried out a replication study of ADHD among 2726 cases and 16299 controls in an independent pediatric cohort. In the multi-trait joint analyses, we found five novel genome-wide significant loci for ADHD, one novel locus for BIP, and ten novel loci for MDD. We further achieved modest replication in our independent pediatric dataset. We conducted fine-mapping and functional annotation through an integrative multi-omics approach and identified causal variants and potential target genes at each novel locus. Gene expression profile and gene-set enrichment analysis further suggested early developmental stage expression pattern and postsynaptic membrane compartment enrichment of candidate genes at the genome-wide significant loci of these neuropsychiatric disorders. Therefore, through a multi-omics approach, we identified novel genetic loci associated with the five neuropsychiatric disorders which may help to better understand the underlying molecular mechanism of neuropsychiatric diseases.
Nuclear import of proteins with nuclear localization signals (NLSs) is mediated by shuttling carriers, the importins. Some cargoes display more than a single NLS, and among these are homeodomain proteins such as Arx, which is critical for development of multiple tissues. Arx has two functional NLSs. The present studies show that several pathways can import Arx via its NLS2, which is within its DNA binding homeodomain. Using an in vitro nuclear import assay, we show that import of Arx via NLS2 can be mediated by importin 1, importin 9, or importin 13, with binding being strongest to importin 1. All binding is sensitive to RanGTP. Experiments based on precise domain deletions indicate that NLS2 binds imp1, imp9, and imp13 and includes both an importin binding subdomain and a regulatory subdomain with arginine residues being important for function. Moreover, Arx can be co-precipitated with these importins when NLS2 is present. Although nuclear import of Arx can be mediated by these three importin s, importin 1 seems to play the major role judging from in vivo small interfering RNA ablations and the in vitro import assay. This is the first evidence to show the role of importin 1 in nuclear import of paired-type homeodomain proteins. We propose a novel and possibly quite general mechanism for nuclear import of paired-type homeodomain proteins which is critical for development.Precise nucleocytoplasmic distribution of the homeodomain superfamily of transcription factors is critical for development. Several studies have demonstrated that NLS activity resides within the 60-amino acid DNA binding homeodomain itself, which is composed of three helices (1, 2). The "paired type" subgroup of the superfamily is characterized by a set of highly conserved residues. There are 26 members of this subgroup in man. The aristaless-related homeobox (ARX) 4 protein, a paired-type homeodomain containing protein, is mutated in multiple human conditions (3-5). ARX is expressed most strongly in the brain (6) and is important for development of the forebrain, pancreas, and testis (7). Arx proteins are highly conserved (Fig. 1) and contain 562 amino acids (564 amino acids in mouse) with four poly(A) (alanine) tracts of variable length, a paired-type homeodomain, and a conserved "aristaless" domain (8). Endogenous Arx was found in the nucleus of some types of nerve cells (9, 10). Because Arx has a molecular mass larger than 60 kDa, its nuclear import is likely to be signal-dependent. Three putative basic NLSs in Arx have been proposed (8, 11): NLS1 from aa 82 to 89, BC1 from aa 327 to 334, and BC2 from aa 381 to 388 (Fig. 1). It is not clear whether or how these putative NLSs function in the nuclear localization of Arx.As for other trinucleotide-repeat-containing genes (12, 13), the first poly(A) tract can expand in Arx. Expansion of this tract or loss of the 3Ј aristaless domain in Arx are both associated with infantile spasms syndrome and mental retardation (14, 15). Moreover, expansion of the first poly(A) tract of Arx results in for...
Glioblastoma (GB) is the most malignant and aggressive form of brain tumor, characterized by frequent hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. PI3K/AKT/mTOR inhibitors have a promising clinical efficacy theoretically. However, strong drug resistance is developed in GB against the PI3K/AKT/mTOR inhibitors due to the cytoprotective effect and the adaptive response of autophagy during the treatment of GB. Activation of autophagy by the PI3K/AKT/mTOR inhibitors not only enhances treatment sensitivity but also leads to cell survival when drug resistance develops in cancer cells. In this review, we analyze how to increase the antitumor effect of the PI3K/AKT/mTOR inhibitors in GB treatment, which is achieved by various mechanisms, among which targeting autophagy is an important mechanism. We review the dual role of autophagy in both GB therapy and resistance against inhibitors of the PI3K/AKT/mTOR signaling pathway, and further discuss the possibility of using combinations of autophagy and PI3K/AKT/mTOR inhibitors to improve the treatment efficacy for GB. Finally, we provide new perspectives for targeting autophagy in GB therapy.
Background Coronavirus disease 2019 (COVID-19) has caused a global pandemic that has raised worldwide concern. This study aims to investigate the correlation between the extent of lung infection and relevant clinical laboratory testing indicators in COVID-19 and to analyse its underlying mechanism. Methods Chest high-resolution computer tomography (CT) images and laboratory examination data of 31 patients with COVID-19 were extracted, and the lesion areas in CT images were quantitatively segmented and calculated using a deep learning (DL) system. A cross-sectional study method was carried out to explore the differences among the proportions of lung lobe infection and to correlate the percentage of infection (POI) of the whole lung in all patients with clinical laboratory examination values. Results No significant difference in the proportion of infection was noted among various lung lobes (P > 0.05). The POI of total lung was negatively correlated with the peripheral blood lymphocyte percentage (L%) (r = − 0.633, P < 0.001) and lymphocyte (LY) count (r = − 0.555, P = 0.001) but positively correlated with the neutrophil percentage (N%) (r = 0.565, P = 0.001). Otherwise, the POI was not significantly correlated with the peripheral blood white blood cell (WBC) count, monocyte percentage (M%) or haemoglobin (HGB) content. In some patients, as the infection progressed, the L% and LY count decreased progressively accompanied by a continuous increase in the N%. Conclusions Lung lesions in COVID-19 patients are significantly correlated with the peripheral blood lymphocyte and neutrophil levels, both of which could serve as prognostic indicators that provide warning implications, and contribute to clinical interventions in patients.
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