Genetic mutations in the gene encoding transport protein particle complex 9 (trappc9), a subunit of TRAPP that acts as a guanine nucleotide exchange factor for rab proteins, cause intellectual disability with brain structural malformations by elusive mechanisms. Here, we report that trappc9-deficient mice exhibit a broad range of behavioral deficits and postnatal delay in growth of the brain. Contrary to volume decline of various brain structures, the striatum of trappc9 null mice was enlarged. An imbalance existed between dopamine D1 and D2 receptor containing neurons in the brain of trappc9-deficient mice; pharmacological manipulation of dopamine receptors improved performances of trappc9 null mice to levels of wild-type mice on cognitive tasks. Loss of trappc9 compromised the activation of rab11 in the brain and resulted in retardation of endocytic receptor recycling in neurons. Our study elicits a pathogenic mechanism and a potential treatment for trappc9-linked disorders including intellectual disability.
To investigate the clinicopathological features and prognostic impact of Fusobacterium nucleatum (F nucleatum) status in patients with colorectal cancer (CRC) and its relationships with microsatellite instability (MSI) status.Retrospective analysis of consecutive 91 CRC tissues from surgically resected specimens of stage III or high-risk stage II CRC patients who had received curative surgery in Wuhan Union Hospital from January, 2017 to January, 2019 was conducted. F nucleatum DNA was quantitatively measured and classified into 1 of the 2 categories: F nucleatum-high, or F nucleatum-low/negative. The Cox risk ratio model analysis was performed to identify independent risk factors of F nucleatum. F nucleatum-high group was compared with the F nucleatum-low/negative group with respect to clinicopathological features and their relationships with MSI status. Kaplan–Meier method and log-rank test were used for univariate analysis of prognostic factors in patients with CRC.The number of total lymph node acquisition and positive lymph nodes, neurological invasion, vascular tumor thrombus were higher in F nucleatum-high group (27.44 ± 25.213 vs 20.70 ± 10.141; P = .018; 3.80 ± 7.974 vs 1.74 ± 3.531; P = .001; 68.0% vs 33.3%; P = .003; 60.0% vs 25.8%; P = .002). Moreover, microsatellite mutations were more frequent in patients with F nucleatum-high (84.0% vs 60.6%; P = .034). A higher abundance of F nucleatum in CRC is associated with a shorter survival time. The F nucleatum status, peripheral nerve invasion, vascular tumor thrombus, lymph node metastasis, and TNM staging were related factors affecting the prognosis of patients with CRC. The Cox risk ratio model analysis showed that the F nucleatum (odds ratio [OR] 2.094, 95% confidence interval [CI] 1.178–8.122, P = .032) and MSI status (OR 2.243, 95% CI 1.136–5.865, P = 0.039) were independent prognostic factors.Intratumoral F nucleatum load has a poor prognostic effect of CRC by increasing nerve invasion, vascular tumor thrombus, and microsatellite mutation.
The comorbidity of diabetes and depression has a negative impact on both lifestyle and quality of life. Astaxanthin (AST) has been demonstrated to improve glucose metabolism and has antidepressant-like effects, but it is not clear whether AST has potential for preventing depression in diabetes. The aim of this study is to observe the preventive and therapeutic effects of AST on glucose metabolism or depressive-like behaviors in a diabetic rat model produced by feeding with a high-fat diet for 10 weeks followed by injection of 25 mg/kg streptozotocin (STZ). Preventive treatment with AST at doses of 7.5, 15, and 25 mg/kg/day was given by intragastric gavage 4 weeks before STZ injection. Preventive plus therapeutic treatment also involved therapeutic AST treatments for 6 more weeks after STZ injection, whereas therapeutic-only treatment involved only the 6-week post-STZ treatment. Depressive-like behaviors were evaluated at the end of the treatment by using open field, locomotor activity, elevated plus maze, and forced swimming tests. Preventive and therapeutic treatment with AST both reduced the level of fasting glucose, improved glucose tolerance, and decreased total TCh and TG in diabetic rats. Preventive or preventative plus therapeutic treatment with AST decreased the immobility time and increased the time spent in the open arms of an elevated plus maze and locomotor activity in diabetic rats. However, therapeutic treatment with AST alone failed to affect the depressive-like behaviors. Preventive or preventative plus therapeutic treatment with AST at doses of 15 or 25 mg/kg significantly increased the expression of pERK, pAKT, pCREB, and BDNF in the prefrontal cortex (PFC) in diabetic rats. In contrast, therapeutic treatment with 25 mg/kg AST alone increased the expression of pERK in the PFC. This study indicates that AST may be used as a preventive or therapeutic approach for comorbidity of diabetes and depression.
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