Differential Protein Expression in Small Intestinal Neuroendocrine Tumors and Liver Metastases

OBJECTIVE: Small intestinal neuroendocrine tumors (SI-NETs) are often detected after they have become metastatic. Using a novel protein array, we identified pathways important in SI-NET metastasis development in surgically resected patients. METHODS: Paired primary tumors and liver metastases from 25 patients undergoing surgical resection for metastatic SI-NETs were harvested. Extracted proteins were separated by sodium dodecyl sulfate gel and multiplex immunoblots were performed with 136 antibodies. Significant Analysis of Microarray was used to select for differentially expressed proteins. A tissue microarray was constructed from 27 archived specimens and stained by immunohistochemistry. RESULTS: Comparing primary SI-NETs with matched normal small-bowel mucosa, 9 proteins were upregulated and cyclin E was downregulated. The SI-NET liver metastases demonstrated upregulation of P-ERK and p27 but downregulation of CDK2 and CDC25B. When comparing primary SI-NET with their paired liver metastases, cyclin E demonstrated a significant upregulation in the liver metastasis. Tissue microarray demonstrated higher p38 expression and lower Cdc 25b expression in SI-NETs versus liver metastases and confirmed higher expression of p27 in liver metastases versus normal liver. CONCLUSIONS: Few studies have compared protein expression in paired primary and metastatic SI-NETs. Our findings reveal changes in a limited number of proteins, suggesting that these may be targets for therapy

Combining task-evoked and spontaneous activity to improve pre-operative brain mapping with fMRI

Noninvasive localization of brain function is used to understand and treat neurological disease, exemplified by pre-operative fMRI mapping prior to neurosurgical intervention. The principal approach for generating these maps relies on brain responses evoked by a task and, despite known limitations, has dominated clinical practice for over 20years. Recently, pre-operative fMRI mapping based on correlations in spontaneous brain activity has been demonstrated, however this approach has its own limitations and has not seen widespread clinical use. Here we show that spontaneous and task-based mapping can be performed together using the same pre-operative fMRI data, provide complimentary information relevant for functional localization, and can be combined to improve identification of eloquent motor cortex. Accuracy, sensitivity, and specificity of our approach are quantified through comparison with electrical cortical stimulation mapping in eight patients with intractable epilepsy. Broad applicability and reproducibility of our approach are demonstrated through prospective replication in an independent dataset of six patients from a different center. In both cohorts and every individual patient, we see a significant improvement in signal to noise and mapping accuracy independent of threshold, quantified using receiver operating characteristic curves. Collectively, our results suggest that modifying the processing of fMRI data to incorporate both task-based and spontaneous activity significantly improves functional localization in pre-operative patients. Because this method requires no additional scan time or modification to conventional pre-operative data acquisition protocols it could have widespread utility

Distinct but overlapping roles of LRRTM1 and LRRTM2 in developing and mature hippocampal circuits

LRRTMs are postsynaptic cell adhesion proteins that have region-restricted expression in the brain. To determine their role in the molecular organization of synapses in vivo, we studied synapse development and plasticity in hippocampal neuronal circuits in mice lacking both Lrrtm1 and Lrrtm2. We found that LRRTM1 and LRRTM2 regulate the density and morphological integrity of excitatory synapses on CA1 pyramidal neurons in the developing brain but are not essential for these roles in the mature circuit. Further, they are required for long-term-potentiation in the CA3-CA1 pathway and the dentate gyrus, and for enduring fear memory in both the developing and mature brain. Our data show that LRRTM1 and LRRTM2 regulate synapse development and function in a cell-type and developmental-stage-specific manner, and thereby contribute to the fine-tuning of hippocampal circuit connectivity and plasticity

Impact of the Kuroshio intrusion on the nutrient inventory in the upper northern South China Sea: insights from an isopycnal mixing model

Based on four cruises covering a seasonal cycle in 2009-2011, we examined the impact of the Kuroshio intrusion, featured by extremely oligotrophic waters, on the nutrient inventory in the central northern South China Sea (NSCS). The nutrient inventory in the upper 100m of the water column in the study area ranged from similar to 200 to similar to 290 mmol m(-2) for N+N (nitrate plus nitrite), from similar to 13 to similar to 24 mmol m(-2) for soluble reactive phosphate and from similar to 210 to similar to 430 mmol m(-2) for silicic acid. The nutrient inventory showed a clear seasonal pattern with the highest value appearing in summer, while the N+N inventory in spring and winter had a reduction of similar to 13 and similar to 30 %, respectively, relative to that in summer. To quantify the extent of the Kuroshio intrusion, an isopycnal mixing model was adopted to derive the proportional contribution of water masses from the SCS proper and the Kuroshio along individual isopycnal surfaces. The derived mixing ratio along the isopycnal plane was then employed to predict the genuine gradients of nutrients under the assumption of no biogeochemical alteration. These predicted nutrient concentrations, denoted as N-m, are solely determined by water mass mixing. Results showed that the nutrient inventory in the upper 100m of the NSCS was overall negatively correlated to the Kuroshio water fraction, suggesting that the Kuroshio intrusion significantly influenced the nutrient distribution in the SCS and its seasonal variation. The difference between the observed nutrient concentrations and their corresponding Nm allowed us to further quantify the nutrient removal/addition associated with the biogeochemical processes on top of the water mass mixing. We revealed that the nutrients in the upper 100m of the water column had a net consumption in both winter and spring but a net addition in fall.Based on four cruises covering a seasonal cycle in 2009-2011, we examined the impact of the Kuroshio intrusion, featured by extremely oligotrophic waters, on the nutrient inventory in the central northern South China Sea (NSCS). The nutrient inventory in the upper 100m of the water column in the study area ranged from similar to 200 to similar to 290 mmol m(-2) for N+N (nitrate plus nitrite), from similar to 13 to similar to 24 mmol m(-2) for soluble reactive phosphate and from similar to 210 to similar to 430 mmol m(-2) for silicic acid. The nutrient inventory showed a clear seasonal pattern with the highest value appearing in summer, while the N+N inventory in spring and winter had a reduction of similar to 13 and similar to 30 %, respectively, relative to that in summer. To quantify the extent of the Kuroshio intrusion, an isopycnal mixing model was adopted to derive the proportional contribution of water masses from the SCS proper and the Kuroshio along individual isopycnal surfaces. The derived mixing ratio along the isopycnal plane was then employed to predict the genuine gradients of nutrients under the assumption of no biogeochemical alteration. These predicted nutrient concentrations, denoted as N-m, are solely determined by water mass mixing. Results showed that the nutrient inventory in the upper 100m of the NSCS was overall negatively correlated to the Kuroshio water fraction, suggesting that the Kuroshio intrusion significantly influenced the nutrient distribution in the SCS and its seasonal variation. The difference between the observed nutrient concentrations and their corresponding Nm allowed us to further quantify the nutrient removal/addition associated with the biogeochemical processes on top of the water mass mixing. We revealed that the nutrients in the upper 100m of the water column had a net consumption in both winter and spring but a net addition in fall

Mus musculus deficient for secretory antibodies show delayed growth with an altered urinary metabolome

© 2019 The Author(s). Background: The polymeric immunoglobulin receptor (pIgR) maintains the integrity of epithelial barriers by transporting polymeric antibodies and antigens through the epithelial mucosa into the lumen. In this study, we examined the role of pIgR in maintaining gut barrier integrity, which is important for the normal development in mice. Methods: Cohorts of pIgR -/- mice and their wildtype controls were housed under Specific Pathogen Free (SPF) conditions and monitored for weight gain as an indicator of development over time. The general physiology of the gastrointestinal tract was analysed using immunohistochemistry in young (8-12 weeks of age) and aged mice (up to 18 months of age), and the observed immunopathology in pIgR -/- mice was further characterised using flow cytometry. Urinary metabolites were analysed using gas chromatography-mass spectrometry (GC-MS), which revealed changes in metabolites that correlated with age-related increase in gut permeability in pIgR -/- mice. Results: We observed that pIgR -/- mice exhibited delayed growth, and this phenomenon is associated with low-grade gut inflammation that increased with ageing. The gross intraepithelial lymphocytic (IEL) infiltration characteristic of pIgR -/- mice was redefined as CD8α+αβ+ T cells, the majority of which expressed high levels of CD103 and CD69 consistent with tissue resident memory T cells (TRM). Comparison of the urinary metabolome between pIgR -/- and wild-type mice revealed key changes in urinary biomarkers fucose, glycine and Vitamin B5, suggestive of altered mucosal permeability. A significant increase in gut permeability was confirmed by analysing the site-specific uptake of sugar probes in different parts of the intestine. Conclusion: Our data show that loss of the secretory antibody system in mice results in enhanced accumulation of inflammatory IELs in the gut, which likely reflects ongoing inflammation in reaction to gut microbiota or food antigens, leading to delayed growth in pIgR -/- mice. We demonstrate that this leads to the presence of a unique urinary metabolome profile, which may provide a biomarker for altered gut permeability

In-Plane Deformation Mechanics for Highly Stretchable Electronics

Scissoring in thick bars suppresses buckling behavior in serpentine traces that have thicknesses greater than their widths, as detailed in a systematic set of analytical and experimental studies. Scissoring in thick copper traces enables elastic stretchability as large as approximate to 350%, corresponding to a sixfold improvement over previously reported values for thin geometries (approximate to 60%).</p

Fracture behaviors under pure shear loading in bulk metallic glasses

Pure shear fracture test, as a special mechanical means, had been carried out extensively to obtain the critical information for traditional metallic crystalline materials and rocks, such as the intrinsic deformation behavior and fracture mechanism. However, for bulk metallic glasses (BMGs), the pure shear fracture behaviors have not been investigated systematically due to the lack of a suitable test method. Here, we specially introduce a unique antisymmetrical four-point bend shear test method to realize a uniform pure shear stress field and study the pure shear fracture behaviors of two kinds of BMGs, Zr-based and La-based BMGs. All kinds of fracture behaviors, the pure shear fracture strength, fracture angle and fracture surface morphology, are systematically analyzed and compared with those of the conventional compressive and tensile fracture. Our results indicate that both the Zrbased and La-based BMGs follow the same fracture mechanism under pure shear loading, which is significantly different from the situation of some previous research results. Our results might offer new enlightenment on the intrinsic deformation and fracture mechanism of BMGs and other amorphous materials

Designing ultrafine lamellar eutectic structure in bimodal titanium alloys by semi-solid sintering

We report on a novel approach to design typical ultrafine lamellar eutectic structure in bimodal alloys fabricated by semi-solid sintering (SSS) of a eutectic mixture. In our work ultrafine lamellar eutectic structure was implemented by controlling the phase composition of eutectic reaction and consequently by regulating the structure of eutectic reaction-induced liquid phase through varying component number. Microstructure analysis indicate that although all SSSed alloys have the same three phase constitutions of bcc beta-Ti(Fe Co) and fcc Ti-2(Co Fe) the morphology and distribution of the eutectic structure transforms from limited length and minor quantity to partial fine alternating bcc beta-Ti and bcc Ti(Fe Co) lamellae and further to typical complete ultrafine alternating continuous lamellae in the SSSed ternary Ti-Fe-Co quaternary Ti-Fe-Co-Nb and quinary Ti-Fe-Co-Nb-Al alloys. Interestingly the SSSed Ti-Fe-Co-Nb-Al alloy presents a novel bimodal microstructure of coarse fcc Ti-2(Co Fe) surrounded by an ultrafine lamellar eutectic matrix containing ultrafine bcc beta-Ti and bcc Ti(Fe Co) lamellae. This bimodal microstructure exhibits ultra-high yield strength of 2050 MPa with plasticity in compression of 19.7% which exceed published values of equivalent materials. Our results provide a novel pathway for fabricating new-structure metallic alloys for high-performance structural applications. (C) 2017 Elsevier B.V. All rights reserved.</p

Differentiation-inducing and anti-proliferative activities of isoliquiritigenin and all-trans-retinoic acid on B16F0 melanoma cells: Mechanisms profiling by RNA-seq

Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of malignant melanoma has significantly increased over the last decade. With the development of therapy, the survival rate of some kind of cancer has been improved greatly. But the treatment of melanoma remains unsatisfactory. Much of melanoma's resistance to traditional chemotherapy is believed to arise intrinsically, by virtue of potent growth and cell survival-promoting genetic alteration. Therefore, significant attention has recently been focused on differentiation, therapy, as well as differentiation inducer compounds. In previous study, we found isoliquiritigenin (ISL), a natural product extracted from licorice, could induce B16F0 melanoma cell differentiation. Here we investigated the transcriptional response of melanoma differentiation process induced by ISL and all-trans-retinoic acid (RA). Results showed that 390 genes involves in 201 biochemical pathways were differentially expressed in ISL treatment and 304 genes in 193 pathways in RA treatment. Differential expressed genes (DGEs, fold-change (FC) >= 10) with the function of anti-proliferative and differentiation inducing indicated a loss of grade malignancy characteristic. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated glutathione metabolism, glycolysis/gluconeogenesis and pentose phosphate pathway were the top three relative pathway perturbed by ISL, and mitogen-activated protein kinase (MAPK) signaling pathway was the most important pathway in RA treatment. In the analysis of hierarchical clustering of DEGs, we discovered 72 DEGs involved in the process of drug action. We thought Cited1, Tgm2, Xaf1, Cd59a, Fbxo2, Adh7 may have critical role in the differentiation of melanoma. The evidence displayed herein confirms the critical role of reactive oxygen species (ROS) in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics. (C) 2016 Elsevier B.V. All rights reserved