Amyloid precursor protein at node of Ranvier modulates nodal formation

Amyloid precursor protein (APP), commonly associated with Alzheimer disease, is upregulated and distributes evenly along the injured axons, and therefore, also known as a marker of demyelinating axonal injury and axonal degeneration. However, the physiological distribution and function of APP along myelinated axons was unknown. We report that APP aggregates at nodes of Ranvier (NOR) in the myelinated central nervous system (CNS) axons but not in the peripheral nervous system (PNS). At CNS NORs, APP expression co-localizes with tenascin-R and is flanked by juxtaparanodal potassium channel expression demonstrating that APP localized to NOR. In APP-knockout (KO) mice, nodal length is significantly increased, while sodium channels are still clustered at NORs. Moreover, APP KO and APP-overexpressing transgenic (APP TG) mice exhibited a decreased and an increased thickness of myelin in spinal cords, respectively, although the changes are limited in comparison to their littermate WT mice. The thickness of myelin in APP KO sciatic nerve also increased in comparison to that in WT mice. Our observations indicate that APP acts as a novel component at CNS NORs, modulating nodal formation and has minor effects in promoting myelination.     

Scorpion Venom Heat-Resistant Peptide (SVHRP) Enhances Neurogenesis and Neurite Outgrowth of Immature Neurons in Adult Mice by Up-Regulating Brain-Derived Neurotrophic Factor (BDNF)

Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2’-dexoxyuridine (BrdU)-positive cells, BrdU- positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP.     

Prognostic Significance of Systemic Inflammation-Based Lymphocyte- Monocyte Ratio in Patients with Lung Cancer: Based on a Large Cohort Study

Increasing evidence indicates cancer-related inflammatory biomarkers show great promise for predicting the outcome of cancer patients. The lymphocyte- monocyte ratio (LMR) was demonstrated to be independent prognostic factor mainly in hematologic tumor. The aim of the present study was to investigate the prognostic value of LMR in operable lung cancer. We retrospectively enrolled a large cohort of patients with primary lung cancer who underwent complete resection at our institution from 2006 to 2011. Inflammatory biomarkers including lymphocyte count and monocyte count were collected from routinely performed preoperative blood tests and the LMR was calculated. Survival analyses were calculated for overall survival (OS) and disease-free survival (DFS). A total of 1453 patients were enrolled in the study. The LMR was significantly associated with OS and DFS in multivariate analyses of the whole cohort (HR = 1.522, 95% CI: 1.275–1.816 for OS, and HR = 1.338, 95% CI: 1.152–1.556 for DFS). Univariate subgroup analyses disclosed that the prognostic value was limited to patients with non-small-cell lung cancer (NSCLC) (HR: 1.824, 95% CI: 1.520–2.190), in contrast to patients with small cell lung cancer (HR: 1.718, 95% CI: 0.946–3.122). Multivariate analyses demonstrated that LMR was still an independent prognostic factor in NSCLC. LMR can be considered as a useful independent prognostic marker in patients with NSCLC after complete resection. This will provide a reliable and convenient biomarker to stratify high risk of death in patients with operable NSCLC.     

Non-contiguous finished genome sequence and description of Sulfurimonas hongkongensis sp. nov., a strictly anaerobic denitrifying,hydrogen- and sulfur-oxidizing chemolithoautotroph isolated from marine sediment

Here, we report a type strain AST-10 representing a novel species Sulfurimonas hongkongensis within Epsilonproteobacteria, which is involved in marine sedimentary sulfur oxidation and denitrification. Strain AST-10^T (= DSM 22096^T = JCM 18418^T) was isolated from the coastal sediment at the Kai Tak Approach Channel connected to Victoria Harbour in Hong Kong. It grew chemolithoautotrophically using thiosulfate, sulfide or hydrogen as the sole electron donor and nitrate as the electron acceptor under anoxic conditions. It was rod-shaped and grew at 15-35°C (optimum at 30°C), pH 6.5-8.5 (optimum at 7.0-7.5), and 10-60 g L^-1 NaCl (optimum at 30 g L^-1). Genome sequencing and annotation of strain AST-10^T showed a 2,302,023 bp genome size, with 34.9% GC content, 2,290 protein-coding genes, and 42 RNA genes, including 3 rRNA genes.     

TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation

Osteosarcoma is one of the most common primary malignancies in bones and is characterized by high metastatic rates. Circulating tumor cells (CTCs) derived from solid tumors can give rise to metastatic lesions, increasing the risk of death in patients with cancer. Here, we used bioinformatics tools to compare the gene expression between CTCs and metastatic lesions in osteosarcoma to identify novel molecular mechanisms underlying osteosarcoma metastasis. We identified TRAIP as a key differentially expressed gene with prognostic significance in osteosarcoma. We demonstrated that TRAIP regulated the proliferation and invasion of osteosarcoma cells. In addition, we found that TRAIP promoted KANK1 polyubiquitination and subsequent degradation, downregulating IGFBP3 and activating the AKT pathway in osteosarcoma cells. These results support the critical role of the TRAIP/KANK1/IGFBP3/AKT signaling axis in osteosarcoma progression and suggest that TRAIP may represent a promising therapeutic target for osteosarcoma.Subject terms: Bone cancer, Oncogenes     

Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Androgen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.Subject terms: Drug development, Translational research     

转反义OsRACK1 基因增强水稻抗旱能力

RACK1是一种多功能支架蛋白, 广泛参与植物生长发育过程的调节。利用反义RNA技术抑制水稻(Oryz a sativa)RACK1基因的表达, 分析了RACK1基因在响应干旱胁迫中的功能。采用实时定量PCR对获得的转基因植株的RACK1基因表达进行分析, 结果表明转基因水稻RACK1基因表达受抑制程度达到50%左右。与非转基因水稻(对照)相比, 转基因水稻耐干旱能力强, 膜脂过氧化程度低且丙二醛的含量少, SOD活性高。这些结果表明, RACK1蛋白负调节水稻对干旱胁迫的耐受过程, 并且这种调节作用在很大程度上与植株体内的氧化还原系统有关。