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Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x(L), Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x(L) and Mcl-1. Expression of Bcl-x(L), Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x

The cleaning potential of selected Chinese bituminous coals during coal preparation was evaluated in terms of coal quality, cleaning grade, and cleanability. The cleaning potentials were determined for coals sampled from a total of six seams, two each in three different general exploration areas in southern Shanxi, China. Distribution maps of resources with different cleaning potential characteristics were prepared using mapping and geographical information software. In each case, the area and calculated reserves for coals having different classifications of cleaning potentials were determined. The total areal extent of the six coals studied is about 410 million m2, and the total reserves of these coals amount to about 1460 million tonnes, which include coals of poor, fair, good, and proficient cleanabilities. The proportion of high-quality coals is about 28.9%. Coals that can be processed into high-quality coals account for about 69.2%. A cleaning potential gradient is proposed for indicating the cleaning potential level, and an equation for calculating it is established. The necessity of processing raw coal of good quality is also to be considered in terms of economics. It does not make economic sense to process coal with an organic sulfur content more than 1.5%, even though it may have a good cleanability.

5-hydroxymethylcytosine (5hmC) is an intermediate stage of DNA de-methylation. Its location in the genome also serves as an important regulatory signal for many biological processes and its levels change significantly with the etiology of Alzheimer's disease (AD). In keeping with this relationship, the TET family of enzymes which convert 5-methylcytosine (5mC) to 5hmC are responsive to the presence of Aβ. Using hMeDIP-seq, we show that there is a genome-wide reduction of 5hmC that is found in neurons but not in astrocytes from 3xTg mice (an AD mouse model). Decreased TET enzymatic activities in the brains of persons who died with AD suggest that this reduction is the main cause for the loss of 5hmC. Overexpression of human TET catalytic domains (hTETCDs) from the TET family members, especially for hTET3CD, significantly attenuates the neurodegenerative process, including reduced Aβ accumulation as well as tau hyperphosphorylation, and improve synaptic dysfunction in 3xTg mouse brain. Our findings define a crucial role of deregulated 5hmC epigenetics in the events leading to AD neurodegeneration.

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging., Circular RNAs are expressed in the brain and show age-dependent expression patterns. Here the authors show the circGRIA1 is expressed in an age-dependent manner in the male macaque brain and serves a functional role in synaptic plasticity.

Loss of mitochondrial homeostasis are evident in Alzheimer's disease (AD)1. However, the underlying mechanisms remain largely elusive. In this study, we report that lncMtDloop, an age-related and conserved long noncoding RNA derived from mitochondrial DNA (mtDNA) D-loop, is crucial for sustaining mitochondrial transcription and homeostasis, and associates with Alzheimer’s pathogenesis. Notably, the level of lncMtDloop expression is diminished in the brains of human AD patients and the 3xTg mouse model, whereas the failure to recruit mitochondrial transcription factor A (TFAM) leads to the deregulated mitochondrial transcription. Restoring lncMtDloop expression not only significantly improves mitochondrial transcription, morphology and function, but also enhances mitophagy, ameliorates AD-like pathology, which these subcellular effects extend to a dramatic reversal of deficits in synaptic and cognitive behaviors of the 3xTg mouse model. Collectively, our findings show the decreased lncMtDloop expression potentiates AD risk, thereby revealing an unexpected mitochondrial mechanism contributing to AD pathogenesis and opens a new door for therapeutic intervention.

A new continuum model is developed to study the influence of surface stress on the behaviors of piezoelectric nanobeams. Different from existing piezoelectric surface models which only consider the surface properties, the proposed model takes surfaceinduced initial fields into consideration. Due to the fact that the surface-induced initial fields are totally different under various boundary conditions, two kinds of beams, the doubly-clamped beam and the cantilever beam, are analyzed. Furthermore, boundary conditions can affect not only the initial state of the piezoelectric nanobeam but also the forms of the governing equations. Based on the Euler-Bernoulli beam theory, the nonlinear Green-Lagrangian strain-displacement relationship is applied. In addition, the surface area change is also considered in the proposed model. The governing equations of the doubly-clamped and cantilever beams are derived by the energy variation principle. Compared with existing Young-Laplace models, the proposed model for the doubly-clamped beam is similar to the Young-Laplace models. However, the governing equation of the cantilever beam derived by the proposed model is very different from that derived by the Young-Laplace models. The behaviors of piezoelectric nanobeams predicted by these two models also have significant discrepancies, which is owing to the surface-induced initial fields in the bulk beam.

Long noncoding RNAs (lncRNAs) mediate important epigenetic regulation in a wide range of biological processes and diseases. We applied comprehensive analyses of RNA-seq and CAGE-seq (cap analysis of gene expression and sequencing) to characterize the dynamic changes in lncRNA expression in rhesus macaque (Macaca mulatta) brain in four representative age groups. We identified 18 anatomically diverse lncRNA modules and 14 mRNA modules representing spatial, age, and sex specificities. Spatiotemporal- and sex-biased changes in lncRNA expression were generally higher than those observed in mRNA expression. A negative correlation between lncRNA and mRNA expression in cerebral cortex was observed and functionally validated. Our findings offer a fresh insight into spatial-, age-, and sex-biased changes in lncRNA expression in macaque brain and suggest that the changes represent a previously unappreciated regulatory system that potentially contributes to brain development and aging.

In this paper, an exact analytical solution is presented for a transversely isotropic functionally graded magneto-electro-elastic (FGMEE) cantilever beam, which is subjected to a uniform load on its upper surface, as well as the concentrated force and moment at the free end. This solution can be applied for any form of gradient distribution. For the basic equations of plane problem, all the partial differential equations governing the stress field, electric, and magnetic potentials are derived. Then, the expressions of Airy stress, electric, and magnetic potential functions are assumed as quadratic polynomials of the longitudinal coordinate. Based on all the boundary conditions, the exact expressions of the three functions can be determined. As numerical examples, the material parameters are set as exponential and linear distributions in the thickness direction. The effects of the material parameters on the mechanical, electric, and magnetic fields of the cantilever beam are analyzed in detail.

Based on the theory of elastic mechanics, a dynamical model of an encapsulated gas microbubble under ultrasound is presented. The dynamical motion of the microbubble is divided into three states: buckled, elastic, and ruptured. The model describes the compression-only behavior appropriately and derives the transient variation of the resonance frequency of the damped oscillation and the relation between the critical rupture radius and initial outer radius. The normal stress in the tangential direction plays the principal role in the rupture and buckling of the encapsulating shell, resulting in likely rupture for a larger microbubble and resistance to rupture for a thicker-shell microbubble. Comparison of proposed dynamical model with Marmottant’s model has been given. The dynamical model can be employed in ultrasound medical diagnostics and therapy of drug incorporation or extravasation through further understanding the influence of the encapsulating shell.

Roots and phonemes are two important ingredients (but not independent ones) when learning the Chinese language. In order to optimize the learning strategy, various key nodes mining algorithms are implemented both in the root network (RN) and phoneme network (PN) of modern Chinese characters. The lists of important roots and phonemes, and eventually the important characters are dug out and suggested. Rather than the commonly used frequency dictionary of characters, one would find that results from the key nodes mining are more systematic. Moreover, roots and phonemes are studied from perspective of the multi-layer network, in the interest of exploring the correlation between them, which are also very useful when learning the Chinese language.

The existing forms of the impurity Nb5+ in the Nb5+:PbWO4 (PWO) crystals are simulated by computer technology. The possible various kinds of defects in the Nb5+:PWO crystals are also simulated. By analyzing the calculation results of defect formation energies and binding energies, the optimal substitution positions of the Nb5+ ions and the charge compensating mechanism [ Nb w - + V O 2 + + Nb w - ] in the Nb5+:PWO crystals were obtained. The electronic structures for Nb5+:PWO were calculated with density functional theory code CASTEP. It shows that the doping of Nb5+ ions could suppress the 350 nm absorption band.

Background: Tumor-specific immunity of insulin-like growth factor-binding protein-2 (IGFBP-2) has been reported in several cancers. We aimed to assess the role of serum IGFBP-2 antibodies (IGFBP-2 Abs) in early cancer detection. Patients and methods: Glioma and colorectal carcinoma (CRC) were used as models. Serum IGFBP-2 and IGFBP-2 Abs were measured in 260 tumor patients (145 gliomas, 45 colorectal polyps, and 70 CRCs) and 141 controls. Receiver operating characteristic curves were applied. Results: Serum IGFBP-2 Ab levels were significantly elevated in tumors (mean: 82 ng/ml, median: 17 ng/ml, range: 0‐1387 ng/ml) compared with controls (11, 0, 0‐212 ng/ml) (P < 0.0001) and higher in early than advanced cancers opposite of serum IGFBP-2 levels. IGFBP-2 Abs effectively discriminated between controls and grade II and III gliomas [area under the curve (AUC): 0.821‐0.864; 95% confidence interval (CI) = 0.762‐0.936; P < 0.0001], and CRC I‐II (AUC: 0.668; 95% CI = 0.566‐0.770; P = 0.002) as well as indicative of advanced polyps at high risk of CRC (AUC: 0.72; 95% CI = 0.630‐0.811; P < 0.0001). The sensitivity and specificity for diagnosing grade II‐III gliomas reached 66%‐84% and 81%. Combined serum IGFBP-2 and IGFBP-2 Abs augmented the discriminative power of all stage tumors (AUC: 0.823), gliomas (AUC: 0.800), and CRCs (AUC = 0.917). Conclusion: Our results first demonstrate IGFBP-2 Abs for early cancer detection and in combination of serum IGFBP-2 for improved cancer diagnosis.

This paper presents novel algorithms for optimal bit allocation and uniform rate control in video coding. By introducing an important factor of the frame picture in the Group of Pictures (GOP), the bit allocation is formulated as a convex programming problem, and is efficiently solved by designed algorithm which combines Lagrangian method and Boundary Linear Search method (L-BLS). Then, an efficient rate control scheme is proposed and is also simulated and verified in the MPEG2 video coding. Experimental results show that the proposed scheme can achieve a better picture quality, namely, PSTN reached average 1.1db improvement than the Test Model5 (TM5) under the same target bits rate and mismatch error.

Because of the limitation of physiological characteristics of human eyes, it is necessary to develop vision enhancement system for maritime search and rescue (SAR-VES), which is intended to improve the poor searching performance of human vision at sea. A system with its framework architecture, which integrate the imaging systems of visible light, infrared, radar and satellite remote sensing, is proposed in this paper to compensate the weakness of the human observation in the maritime search and rescue environment. The system will promote the sensitivity and the detection rate of targets, especially small ones, at sea. It will help improve the safety of life at sea and reduce economical losses in marine accidents.

Background The role of Th17 cells in colorectal tumorigenesis and development still remains unclear, despite the fact that it has been established in the pathogenesis of autoimmune diseases. Methods We first analyzed Th17 cells and Treg cells using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls, and the frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) stimulated by anti-CD3 plus anti-CD28 and treated by IL-1β, IL-6, and TGF-β in different concentrations. We then detected cytokines IL-1β, IL-6, IL-17A, IL-21, IL-23 or TGF-β by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo. Results It was found that the percentage of Th17 and Treg cells increased in the circulation of both CRA and CRC patients; the increase of Th17 cells in the circulation occurred in early stages, whereas the increase of Treg cells in the circulation and the increase of Th17 cells in tumor tissues occurred in advanced stages. The subsequent cytokine profiling showed that, along CRC progression, IL-1β, IL-17A and IL-23 underwent a similar change, while IL-6 in CRC exhibited an opposite change, with Th17 cells. In addition, high levels of TGF-β and IL-17A were detected in tumor tissues rather than in normal mucosa. The in vitro experiment further demonstrated that IL-1β, IL-6 or TGF-β modulated Th17 cell expansion in PBMC. Conclusions Our study reveals a unique change of Th17 cells, which is regulated possibly by IL-1β, IL-6 and TGF-β in the progression of CRC.

Background: Tumor-specific immunity of insulin-like growth factor binding protein-2 (IGFBP-2) has been reported in several cancers. We aimed to assess the role of serum IGFBP-2 antibodies (IGFBP-2-Abs) in early cancer detection. Patients and Methods: Glioma and colorectal carcinoma (CRC) were used as models. Serum IGFBP-2 and IGFBP-2-Abs were measured in 260 tumor patients (145 gliomas, 45 colorectal polyps, and 70 CRCs) and 141 controls. Receiver operating characteristic curves were applied. Results: Serum IGFBP-2-Ab levels were significantly elevated in tumors (mean: 82.1 ng/ml, median: 17 ng/ml, range: 0-1,387 ng/ml) compared with controls (10.6 ng/ml, 0 ng/ml, 0-212 ng/ml) (P < 0.0001), and higher in early than advanced cancers opposite of serum IGFBP-2 levels. IGFBP-2-Abs effectively discriminated between controls and grade II and III gliomas [area under the curve (AUC): 0.821-0.864; 95% confidence interval (CI) = 0.762-0.936; P < 0.0001], and CRC I-II (AUC: 0.668; 95% CI = 0.566-0.770; P = 0.002) as well as indicative of advanced polyps at high risk of CRC (AUC: 0.72; 95% CI = 0.630-0.811; P < 0.0001). The sensitivity and specificity for diagnosing grade II-III gliomas reached 66.2% - 83.8% and 81%. Combined serum IGFBP-2 and IGFBP-2-Abs augmented the discriminative power of all stage tumors (AUC: 0.823), gliomas (AUC: 0.800), and CRCs (AUC = 0.917). Conclusions: Our results first demonstrate IGFBP-2-Abs for early cancer detection, and in combination of serum IGFBP-2 for improved cancer diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4520. doi:1538-7445.AM2012-4520