TMPRSS4 (Transmembrane protease serine 4) is up-regulated in a broad spectrum of cancers. However, little is known about the biological effects of TMPRSS4 on hepatocellular carcinoma (HCC) and the related mechanisms. In the present study, we found that overexpression of TMPRSS4 significantly promoted the invasion, migration, adhesion and metastasis of HCC. Further more, TMPRSS4 induced EMT of HCC, which was mediated via snail and slug as a result of Raf/MEK/ERK1/2 activation, and inhibition of ERK1/2 activation by its inhibitor was associated with reduced cell invasion and reversion of EMT. In addition, we demonstrated that TMPRSS4 remarkably suppressed the expression of RECK, an inhibitor of angiogenesis, and drastically induced tumor angiogenesis and growth. More important, in clinical HCC specimens, TMPRSS4 expression was significantly correlated with tumor staging and was inversely correlated with E-cadherin and RECKS expression. Expression of TMPRSS4 is significantly associated with HCC progression and is an independent prognostic factor for postoperative worse survival and recurrence. In conclusion, TMPRSS4 functions as a positive regulator of Raf/MEK/ERK1/2 pathway and promotes HCC progression by inducing EMT and angiogenesis. The increase of TMPRSS4 expression may be a key event for HCC progression and may be regarded as a potential prognostic marker for HCC.

Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α - 1, α -2/δ, β, and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR = 0.856, P = 5.43 × 10(-5)). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR = 0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P = 1.4 × 10(-6)) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted, and significant statistical interaction (OR = 0.622, P = 2.93 × 10(-6), Pperm < 0.001) was observed between rs192808 (CACNG6) and rs2048137 (CACNG5). Our results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes.

The 5-HT1A receptor (HTR1A) and the 5-HT5A receptor (HTR5A) are key 5-HT receptors with distinct inhibitory functions. Studies have been conducted to investigate the association of a few HTR1A polymorphisms with schizophrenia, producing conflicting results, and the relationship between HTR5A and schizophrenia has not yet been well investigated. We aimed to examine the association of HTR1A and HTR5A with schizophrenia and executive function. The study included a discovery stage with 1,115 patients and 2,289 controls and a replication stage with 2,128 patients and 3,865 controls. A total of 30 common SNPs in HTR1A and HTR5A were genotyped in the discovery stage, and significantly associated SNPs were genotyped in the replication stage. We identified that two SNPs (rs878567 in HTR1A and rs1800883 in HTR5A) were significantly associated with schizophrenia in both datasets, and similar results were observed in imputation and haplotype association analyses. Moreover, we found that SNP rs1800883 significantly interacted with executive function when processing the perseverative error of Wisconsin Card Sorting Test in patients. Our results provide further supportive evidence of the effect of HTR1A and HTR5A on the etiology of schizophrenia and suggest that the selected genetic variations in HTR5A may be involved in impaired executive function.

A major limitation in the development of effective scaffolds for bone regeneration has been the limited vascularization of the regenerating tissue. Here, we propose the development of a novel calcium phosphate cement (CPC)-based scaffold combining the properties of mesoporous silica (MS) with recombinant human bone morphogenic protein-2 (rhBMP-2) to facilitate vascularization and osteogenesis. Specifically, the development of a custom MS/CPC paste allowed the three-dimensional (3D) printing of scaffolds with a defined macroporous structure and optimized silicon (Si) ions release profile to promote the ingrowth of vascular tissue at an early stage after implantation in support of tissue viability and osteogenesis. In addition, the scaffold microstructure allowed the prolonged release of rhBMP-2, which in turn significantly stimulated the osteogenesis of human bone marrow stromal cells in vitro and of bone regeneration in vivo as shown in a rabbit femur defect repair model. Thus, the combination MS/CPC/rhBMP-2 scaffolds might provide a solution to issues of tissue necrosis during the regeneration process and therefore might be able to be readily developed into a useful tool for bone repair in the clinic.

The heritability of schizophrenia (SCZ) has been estimated to be as high as 80%, suggesting that genetic factors may play an important role in the etiology of SCZ. Cav1.2 encoded by CACNA1C and Cav1.3 encoded by CACNA1D are dominant calcium channel-forming subunits of L-type Voltage-dependent Ca(2+) channels, expressed in many types of neurons. The CACNA1C has been consistently found to be a risk gene for SCZ, but it is unknown for CACNA1D. To investigate the association of CACNA1D with SCZ, we designed a two-stage case-control study, including a testing set with 1117 cases and 1815 controls and a validation set with 1430 cases and 4295 controls in Han Chinese. A total of selected 97 tag single nucleotide polymorphisms (SNPs) in CACNA1D were genotyped, and single-SNP association, imputation analysis and gender-specific association analyses were performed in the two independent datasets. None was found to associate with SCZ. Further genotype and haplotype association analyses indicated a similar pattern in the two-stage study. Our findings suggested CACNA1D might not be a risk gene for SCZ in Han Chinese population, which add to the current state of knowledge regarding the susceptibility of CACNA1D to SCZ.

Categorizing 'deficit schizophrenia' (DS) as distinct from 'non-deficit' schizophrenia (NDS) may help reduce heterogeneity within schizophrenia. However, it is unknown if DS has a discrete white matter signature. Here we used MRI to compare white matter volume (voxel-based morphometry) and microstructural integrity (fractional anisotropy, FA) in first-episode treatment-naïve patients with DS and NDS and their unaffected relatives to control groups of similar age. We found that white matter disruption was prominent in DS compared to controls; the DS group had lower volumes in the cerebellum, bilateral extra-nuclear and bilateral frontoparietal regions, and lower FA in the body of corpus callosum, posterior superior longitudinal fasciculus and uncinate fasciculus. The DS group also had lower volume in bilateral extra-nuclear regions compared to NDS, and the volume of these clusters was negatively correlated with deficit symptom ratings. NDS patients however, had no significant volume alterations and limited disruption of microstructural integrity compared to controls. Finally, first-degree relatives of those with DS shared volume abnormalities in right extra-nuclear white matter. Thus, white matter pathology in schizophrenia is most evident in the deficit condition, and lower extra-nuclear white matter volumes in both DS patients and their relatives may represent a brain structural 'endophenotype' for DS.

Nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a therapeutic target in many diseases, because it can induce antioxidant enzymes and other cytoprotective enzymes. Moreover, some Nrf2 activators have strong anti-inflammatory activities. Oxidative stress and inflammation are major components involved in the pathology of diabetic nephropathy. In the present study, we evaluated the Nrf2-dependent anti-oxidative and anti-inflammatory effects of digitoflavone in streptozotocin-induced diabetic nephropathy. The molecular mechanisms of digitoflavone were investigated in vitro using SV40-transformed mouse mesangial cells (SV40-Mes13). For the in vivo experiment, diabetes was induced in Nrf2+/+ and Nrf2-/- mice by STZ injection, and digitoflavone was administered 2 weeks after the STZ injection. Digitoflavone induced Nrf2 activation and decreased oxidative damage, inflammation, TGF-β1 expression, extracellular matrix protein expression, and mesangial cell hyperplasia in SV40-Mes13 cells. Digitoflavone-treated Nrf2+/+ mice, but not Nrf2-/- mice, showed attenuated common metabolic disorder symptoms, improved renal performance, minimized pathological alterations, and decreased oxidative damage, inflammatory gene expression, inflammatory cell infiltration, TGF-β1 expression, and extracellular matrix protein expression. Our results show that the anti-oxidative and anti-inflammatory effects of digitoflavone are mediated by Nrf2 activation and that digitoflavone can be used therapeutically to improve metabolic disorders and relieve renal damage induced by diabetes.

This study was to explore the association between gene variants and p21 expression and investigate the TP53-independent p21 regulation in hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) patients from Guangxi by genome-wide association study. 426 HBV-related HCC patients were enrolled. Results showed that, after quality control, a total of 21,643 SNPs were identified in 107 p21 positive and 298 p21 negative patients. The variants of epidermal growth factor receptor (EGFR; rs2227983 and rs6950826) and spectrin repeat containing, nuclear envelope 2 (SYNE2; rs8010699, rs4027405 and rs1890908) were associated with p21 expression. Moreover the haplotype block (rs2227983 and rs6950826, r(2) = 0.378) in EGFR and the haplotype block in SYNE2 (rs8010699 was in strong LD with rs4027405 and rs1890908 (r(2) = 0.91 and 0.70, respectively)) were identified, and the haplotype A-G of EGFR and haplotype G-A-A of SYNE2 were significantly associated with p21 expression (P < 0.01). rs4027405 and rs1890908 were significantly associated with overall survival, and patients with AG/GG genotypes of SYNE2 gene had a worse overall survival (P = 0.001, P = 0.002). Our findings indicate that variants of EGFR and SYNE2 play an important role in p21 regulation and are associated with the clinical outcome of HBV-related HCC in a TP53-indenpdent manner.

Physical and chemical insult-induced bone marrow (BM) damage often leads to lethality resulting from the depletion of hematopoietic stem and progenitor cells (HSPCs) and/or a deteriorated BM stroma. Notch signaling plays an important role in hematopoiesis, but whether it is involved in BM damage remains unclear. In this study, we found that conditional disruption of RBP-J, the transcription factor of canonical Notch signaling, increased irradiation sensitivity in mice. Activation of Notch signaling with the endothelial cell (EC)-targeted soluble Dll1 Notch ligand mD1R promoted BM recovery after irradiation. mD1R treatment resulted in a significant increase in myeloid progenitors and monocytes in the BM, spleen and peripheral blood after irradiation. mD1R also enhanced hematopoiesis in mice treated with cyclophosphamide, a chemotherapeutic drug that induces BM suppression. Mechanistically, mD1R increased the proliferation and reduced the apoptosis of myeloid cells in the BM after irradiation. The β chain cytokine receptor Csf2rb2 was identified as a downstream molecule of Notch signaling in hematopoietic cells. mD1R improved hematopoietic recovery through up-regulation of the hematopoietic expression of Csf2rb2. Our findings reveal the role of Notch signaling in irradiation- and drug-induced BM suppression and establish a new potential therapy of BM- and myelo-suppression induced by radiotherapy and chemotherapy.

Macrophages have been recognized as an important inflammatory component in choroidal neovascularization (CNV). However, it is unclear how these cells are activated and polarized, how they affect angiogenesis and what the underlining mechanisms are during CNV. Notch signaling has been implicated in macrophage activation. Previously we have shown that inducible disruption of RBP-J, the critical transcription factor of Notch signaling, in adult mice results in enhanced CNV, but it is unclear what is the role of macrophage-specific Notch signaling in the development of CNV. In the current study, by using the myeloid specific RBP-J knockout mouse model combined with the laser-induced CNV model, we show that disruption of Notch signaling in macrophages displayed attenuated CNV growth, reduced macrophage infiltration and activation, and alleviated angiogenic response after laser induction. The inhibition of CNV occurred with reduced expression of VEGF and TNF-α in infiltrating inflammatory macrophages in myeloid specific RBP-J knockout mice. These changes might result in direct inhibition of EC lumen formation, as shown in an in vitro study. Therefore, clinical intervention of Notch signaling in CNV needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.

The genera Anastrepha, Bactrocera, Ceratitis, Dacus and Rhagoletis in the family Tephritidae order Diptera are economically important, worldwide distributed and cause damage to a large number of commercially produced fruits and vegetables. China had regulated these five genera as quarantine pests, including the species Carpomya vesuviana. An accurate molecular method not depending on morphology able to detect all the quarantine fruit flies simultaneously is required for quarantine monitoring. This study contributes a comparative analysis of 146 mitochondrial genomes of Diptera species and found variable sites at the mt DNA cox2 gene only conserved in economically important fruit flies species. Degenerate primers (TephFdeg/TephR) were designed specific for the economically important fruit flies. A 603 bp fragment was amplified after testing each of the 40 selected representative species belonging to each economically important Tephritid genera, no diagnostic fragments were detected/amplified in any of the other Tephritidae and Diptera species examined. PCR sensitivity assays demonstrated the limit of detection of targeted DNA was 0.1 ng/μl. This work contributes an innovative approach for detecting all reported economically important fruit flies in a single-step PCR specific for reported fruit fly species of quarantine concern in China.

Colorectal cancer is the third leading cause of cancer death worldwide. 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapies for treatment of solid tumours, including colorectal cancer. The efficacy of treatment is dependent on tumour type and can only be determined six weeks after beginning chemotherapy, with only 40-50% of patients responding positively to the 5-FU therapy. In this paper, we demonstrate the potential of using Magnetic Resonance (MR) Chemical Shift Imaging (CSI) for in-vivo monitoring of 5-FU tumor-retention in two different colorectal tumour types (HT-29 & H-508). Time curves for 5-FU signals from the liver and bladder were also acquired. We observed significant differences (p < 0.01) in 5-FU signal time dependencies for the HT-29 and H-508 tumours. Retention of 5-FU occurred in the H-508 tumour, whereas the HT-29 tumour is not expected to retain 5FU due to the observation of the negative b time constant indicating a decline in 5FU within the tumour. This study successfully demonstrates that CSI may be a useful tool for early identification of 5-FU responsive tumours based on observed tumour retention of the 5-FU.

Accurate identification of in vivo nonlinear, anisotropic mechanical properties of the aortic wall of individual patients remains to be one of the critical challenges in the field of cardiovascular biomechanics. Since only the physiologically loaded states of the aorta are given from in vivo clinical images, inverse approaches, which take into account of the unloaded configuration, are needed for in vivo material parameter identification. Existing inverse methods are computationally expensive, which take days to weeks to complete for a single patient, inhibiting fast feedback for clinicians. Moreover, the current inverse methods have only been evaluated using synthetic data. In this study, we improved our recently developed multi-resolution direct search (MRDS) approach and the computation time cost was reduced to 1~2 hours. Using the improved MRDS approach, we estimated in vivo aortic tissue elastic properties of two ascending thoracic aortic aneurysm (ATAA) patients from pre-operative gated CT scans. For comparison, corresponding surgically-resected aortic wall tissue samples were obtained and subjected to planar biaxial tests. Relatively close matches were achieved for the in vivo-identified and ex vivo-fitted stress-stretch responses. It is hoped that further development of this inverse approach can enable an accurate identification of the in vivo material parameters from in vivo image data.

Mental effort is a common phenomenological construct deeply linked to volition and self-control. While it is often assumed that the amount of exertion invested in a task can be voluntarily regulated, the neural bases of such faculty and its behavioural effects are yet insufficiently understood. In this study, we investigated how the instructions to execute a demanding cognitive task either "with maximum exertion" or "as relaxed as possible" affected performance and brain activity. The maximum exertion condition, compared to relaxed execution, was associated with speeded motor responses without an accuracy trade-off, and an amplification of both task-related activations in dorsal frontoparietal and cerebellar regions, and task-related deactivations in default mode network (DMN) areas. Furthermore, the visual cue to engage maximum effort triggered an anticipatory widespread increase of activity in attentional, sensory and executive regions, with its peak in the brain stem reticular activating system. Across individuals, this surge of activity in the brain stem, but also in medial wall cortical regions projecting to the adrenal medulla, positively correlated with increases in heart rate, suggesting that the intention to willfully modulate invested effort involves mechanisms related to catecholaminergic transmission and a suppression of DMN activity in favor of externally-directed attentional processes.

Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient's quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24 h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.

China is a mainland country rich in natural morel recourses, having records of half of the worldwide 61 morel phylospecies. In this study, 31 collections of ascocarps from the north Qinling Mountains, 4 collections of commercial cultivars from the south Qinling Mountains, and 3 Morchella mycelium clones from commercial cultivars were investigated using the genealogical concordance phylogenetic species recognition (GCPSR) method. Maximum-likelihood was employed for the construction of phylogenetic trees. A total of five phylogenetic species were found among the 38 collections, namely Morchella sp. Mes-8, Mes-9, Mes-13, and Mes-25, and Morchella chensiensis (IF556780), in addition to the false morel (Verpa bohemica). The identification of cultivated Morchella sp. Mel-2, Mel-6, Mel-10, and Mel-12 coincided with that of the commercial farms. A total of 80% (4/5) of yellow morels were new records for the Qinling region, except Mes-19; moreover, a novel monophyletic lineage, Morchella chensiensis, was found to be distinct from the previously reported phylospecies by single gene and combined genes analysis, thus being herein proposed as a new phylospecies. All collections from this study showed continental endemism, and all Qinling Mountains collections were grouped together in rDNA phylogenetic trees. The study provided insights on biodiversities in this key region of China.

Gamma-Aminobutyric acid (GABA) accumulates in plants following exposure to heavy metals. To investigate the role of GABA in cadmium (Cd) tolerance and elucidate the underlying mechanisms, GABA (0, 25 and 50 µM) was applied to Cd-treated maize plants. Vegetative growth parameters were improved in both Cd-treated and control plants due to GABA application. Cd uptake and translocation were considerably inhibited by GABA. Antioxidant enzyme activity was enhanced in plants subjected to Cd. Concurrently GABA caused further increases in catalase and superoxide dismutase activities, which led to a significant reduction in hydrogen peroxide, superoxide anion and malondealdehyde contents under stress conditions. Polyamine biosynthesis-responsive genes, namely ornithine decarboxylase and spermidine synthase, were induced by GABA in plants grown under Cd shock. GABA suppressed polyamine oxidase, a gene related to polyamine catabolism, when plants were exposed to Cd. Consequently, different forms of polyamines were elevated in Cd-exposed plants following GABA application. The maximum quantum efficiency of photosystem II (Fv/Fm) was decreased by Cd-exposed plants, but was completely restored by GABA to the same value in the control. These results suggest a multifaceted contribution of GABA, through regulation of Cd uptake, production of reactive oxygen species and polyamine metabolism, in response to Cd stress.

Recent global deregulation of ginseng as the table food raises our concern about the possible ginseng-warfarin interaction that could be life-threatening to patients who take warfarin for preventing fatal strokes and thromboembolism while using ginseng products for bioenergy recovery. Here we show that quality-control ginsenosides, extracted from ginseng and containing its major active ingredients, produce dose- and time-dependent antagonism in rats against warfarin's anti-coagulation assessed by INR and rat thrombosis model. The interactions between ginsenosides and warfarin on thrombosis, pharmacokinetics, activities of coagulation factors and liver cytochrome P450 isomers are determined by using thrombosis analyzer, UPLC/MS/MS, ELISA and real-time PCR, respectively. The antagonism correlates well with the related pharmacokinetic interaction showing that the blood plateaus of warfarin reached by one-week warfarin administration are significantly reduced after three-week co-administration of warfarin with ginsenosides while 7-hydroxywarfarin is increased. The one-week warfarin and three-week warfarin-ginsenosides regimen result in restoring the suppressed levels by warfarin of the coagulating factors II, VII and protein Z, and significantly enhance activities of P450 3A4 and 2C9 that metabolize warfarin. The present study, for the first time, provides the solid evidence to demonstrate the warfarin-ginsenoside interaction, and warns the warfarin users and regulation authorities of the dangerous interaction.

Phosphorus stress was applied to enhance the lipid production in Scenedesmus sp. The highest lipid production (350 mg L-1) and lipid content (approximately 41.0% of dry weight) were obtained by addition of 2 mg L-1 NaH2PO4·2H2O every 2 days, which were higher than those in replete phosphorus. Correspondingly, carbohydrate content decreased significantly. We speculated that phosphorus limitation could block starch biosynthesis, and photosynthate flow tended to fatty acid biosynthesis to cope with stress. To investigate the mechanism that phosphorus stress triggers the carbon fixation to lipid biosynthesis, the transcriptome analysis was carried out by the Illumina RNA-seq platform. A total of 2897 genes were identified as differentially expressed genes. The observed overexpression of lipid production under phosphorus stress was bolstered by up-regulation of genes encoding for DGAT and pyruvate kinase, activation of carbohydrate metabolism pathway and fatty acid biosynthesis, and repression of carbohydrate synthesis-presumably to shunt the carbon flux toward TAG biosynthesis. The transcriptome will be useful to understand the lipid metabolism pathway and obtain the engineering economic algae species aimed at biodiesel production.

Intracerebral hemorrhage (ICH) is a serious public health problem with high rates of death and disability. The neuroprotective effect of Growth Differentiation Factor 11 (GDF11) in ICH has been initially proved by our previous study. Oxidative stress (OS) plays crucial roles in mediating subsequent damage of ICH. However, whether and how mitochondrial dynamic events and function participated in ICH pathophysiology, and how mitochondrial function and OS interreacted in the neuroprotective process of GDF11 in ICH remains unclarified. Based on the rat model of ICH and in vitro cell model, we demonstrated that GDF11 could alleviate ICH induced neurological deficits, brain edema, OS status, neuronal apoptosis and inflammatory reaction. In addition, mitochondrial functional and structural impairments were obviously restored by GDF11. Treatment with antioxidant protected against erythrocyte homogenate (EH) induced cell injury by restoring OS status and mitochondrial fusion fission imbalance, which was similar to the effect of GDF11 treatment. Further, inhibition of mitochondrial division with Mdivi-1 attenuated mitochondrial functional defects and neuronal damages. In conclusion, our results for the first time proposed that GDF11 protected the post-ICH secondary injury by suppressing the feedback loop between mitochondrial ROS production and mitochondrial dynamic alteration, resulting in attenuated mitochondrial function and amelioration of neural damage.