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In this paper, we study a priori error estimates for the finite element approximation of the nonlinear Schr\"{o}dinger-Poisson model. The electron density is defined by an infinite series over all eigenvalues of the Hamiltonian operator. To establish the error estimate, we present a unified theory of error estimates for a class of nonlinear problems. The theory is based on three conditions: 1) the original problem has a solution $u$ which is the fixed point of a compact operator $\Ca$, 2) $\Ca$ is Fr\'{e}chet-differentiable at $u$ and $\Ci-\Ca'[u]$ has a bounded inverse in a neighborhood of $u$, and 3) there exists an operator $\Ca_h$ which converges to $\Ca$ in the neighborhood of $u$. The theory states that $\Ca_h$ has a fixed point $u_h$ which solves the approximate problem. It also gives the error estimate between $u$ and $u_h$, without assumptions on the well-posedness of the approximate problem. We apply the unified theory to the finite element approximation of the Schr\"{o}dinger-Poisson model and obtain optimal error estimate between the numerical solution and the exact solution. Numerical experiments are presented to verify the convergence rates of numerical solutions., Comment: 20 pages

User selection has become crucial for decreasing the communication costs of federated learning (FL) over wireless networks. However, centralized user selection causes additional system complexity. This study proposes a network intrinsic approach of distributed user selection that leverages the radio resource competition mechanism in random access. Taking the carrier sensing multiple access (CSMA) mechanism as an example of random access, we manipulate the contention window (CW) size to prioritize certain users for obtaining radio resources in each round of training. Training data bias is used as a target scenario for FL with user selection. Prioritization is based on the distance between the newly trained local model and the global model of the previous round. To avoid excessive contribution by certain users, a counting mechanism is used to ensure fairness. Simulations with various datasets demonstrate that this method can rapidly achieve convergence similar to that of the centralized user selection approach.

The enhanced X-ray Timing and Polarimetry mission (eXTP) is a flagship observatory for X-ray timing, spectroscopy and polarimetry developed by an International Consortium. Thanks to its very large collecting area, good spectral resolution and unprecedented polarimetry capabilities, eXTP will explore the properties of matter and the propagation of light in the most extreme conditions found in the Universe. eXTP will, in addition, be a powerful X-ray observatory. The mission will continuously monitor the X-ray sky, and will enable multiwavelength and multi-messenger studies. The mission is currently in phase B, which will be completed in the middle of 2022.

Localization microscopy offers resolutions down to a single nanometer but currently requires additional dedicated hardware or fiducial markers to reduce resolution loss from the drift of the sample. Drift estimation without fiducial markers is typically implemented using redundant cross correlation (RCC). We show that RCC has sub-optimal precision and bias, which leaves room for improvement. Here, we minimize a bound on the entropy of the obtained localizations to efficiently compute a precise drift estimate. Within practical compute-time constraints, simulations show a 5x improvement in drift estimation precision over the widely used RCC algorithm. The algorithm operates directly on fluorophore localizations and is tested on simulated and experimental datasets in 2D and 3D. An open source implementation is provided, implemented in Python and C++, and can utilize a GPU if available., Team Carlas Smith, BN/Chirlmin Joo Lab

Localization microscopy offers resolutions down to a single nanometer but currently requires additional dedicated hardware or fiducial markers to reduce resolution loss from the drift of the sample. Drift estimation without fiducial markers is typically implemented using redundant cross correlation (RCC). We show that RCC has sub-optimal precision and bias, which leaves room for improvement. Here, we minimize a bound on the entropy of the obtained localizations to efficiently compute a precise drift estimate. Within practical compute-time constraints, simulations show a 5x improvement in drift estimation precision over the widely used RCC algorithm. The algorithm operates directly on fluorophore localizations and is tested on simulated and experimental datasets in 2D and 3D. An open source implementation is provided, implemented in Python and C++, and can utilize a GPU if available., Team Carlas Smith, BN/Chirlmin Joo Lab

ObjectivesTo compare prevalence and severity of diaper dermatitis (DD) in infants and toddlers (babies) across three countries (China, USA, and Germany), including diapered skin measures and caregiver practices.MethodsA cross-sectional study of 1791 babies (~600 from each country) was recruited at each clinical site. Based on regional toilet-training habits, exclusively diaper-wearing infants were recruited between ages 2-8 months in China and 2-18 months in the USA and Germany. DD was measured, as well as skin pH, transepidermal water loss (TEWL), and relative humidity (RH) in the diapered region. Caregiver habits were collected via a questionnaire and included information on hygienic practices.ResultsDiaper dermatitis was highest in the perianal area, followed by the intertriginous, genital, and buttock regions. In general, DD was significantly lower in babies in China, highest in Germany, and intermediate in the USA. This rank ordering of DD by geography was also observed in baby age 2-8 months. The lower DD observed in China was associated with lower skin pH and TEWL on diapered skin and decreased RH in the diaper. Chinese caregivers had the highest rate of prophylactic topical product usage, the most robust cleaning of the diapered area, lack of cleansing after urine-only diaper changes, and Chinese infants spent the least time in an overnight diaper.ConclusionsThese data suggest caregiver behaviors including prophylactic use of topical products, thorough cleaning after stooling and reduced time in an overnight diaper are associated with less DD, lower superficial skin pH, and enhanced skin barrier.

Sea-level changes are an important factor controlling the formation process of bauxite in northern Guizhou. So, research was carried out on the relationship between sea-level changes and the natural types of bauxite ore in the Wuchuan-Zhengan-Daozhen area (WZD) in northern Guizhou by comprehensive use of field geological investigation, hand specimen observation, microscopic observation and regional stratigraphic correlation based on previous studies. The results show that the natural types of ore can be regarded as marker bed of sea-level changes, and earthy ore bed can be seen as a sign of long-standing regression. The WZD area has experienced at least 4 regressions, and the 4 large-scale regressions were an important cause for the formation of high-quality bauxite. Land and sea transition bauxite has similar structural features, and the natural types of ore in all sedimentary bauxite can be used to distinguish the sedimentation cycle of the ore-bearing rock formations. Sedimentary bauxite itself can be regarded as a multi-stage exposure marker bed., Sea-level changes are an important factor controlling the formation process of bauxite in northern Guizhou. So, research was carried out on the relationship between sea-level changes and the natural types of bauxite ore in the Wuchuan-Zhengan-Daozhen area (WZD) in northern Guizhou by comprehensive use of field geological investigation, hand specimen observation, microscopic observation and regional stratigraphic correlation based on previous studies. The results show that the natural types of ore can be regarded as marker bed of sea-level changes, and earthy ore bed can be seen as a sign of long-standing regression. The WZD area has experienced at least 4 regressions, and the 4 large-scale regressions were an important cause for the formation of high-quality bauxite. Land and sea transition bauxite has similar structural features, and the natural types of ore in all sedimentary bauxite can be used to distinguish the sedimentation cycle of the ore-bearing rock formations. Sedimentary bauxite itself can be regarded as a multi-stage exposure marker bed.

A mathematical calculation model of a shearer and a scraper conveyor has been established. Based on the model and the real-time motion trajectory of the shearer, along with measurements of the pitch angles of 4-6 middle troughs, the pitch angle of the next section can be calculated by rolling, and thus the shape of a scraper conveyor obtained. The method was programmed into the bottom layer of the Unity3D software. Data visualisation driving technology was used to produce a real-time display and updating of virtual images. The method was verified experimentally, with the results producing an error between the calculated and actual layout forms of the scraper conveyor of less than 15 mm. The actual operation state of the equipment remains synchronised in real time with the equipment in the virtual monitoring screen. It was shown that the detection accuracy satisfies the practical requirements., A mathematical calculation model of a shearer and a scraper conveyor has been established. Based on the model and the real-time motion trajectory of the shearer, along with measurements of the pitch angles of 4-6 middle troughs, the pitch angle of the next section can be calculated by rolling, and thus the shape of a scraper conveyor obtained. The method was programmed into the bottom layer of the Unity3D software. Data visualisation driving technology was used to produce a real-time display and updating of virtual images. The method was verified experimentally, with the results producing an error between the calculated and actual layout forms of the scraper conveyor of less than 15 mm. The actual operation state of the equipment remains synchronised in real time with the equipment in the virtual monitoring screen. It was shown that the detection accuracy satisfies the practical requirements.

Small interfering RNAs (siRNAs) promote RNA degradation in a variety of processes and have important clinical applications. siRNAs direct cleavage of target RNAs by guiding Argonaute2 (AGO2) to its target site. Target site accessibility is critical for AGO2-target interactions, but how target site accessibility is controlled in vivo is poorly understood. Here, we use live-cell single-molecule imaging in human cells to determine rate constants of the AGO2 cleavage cycle in vivo. We find that the rate-limiting step in mRNA cleavage frequently involves unmasking of target sites by translating ribosomes. Target site masking is caused by heterogeneous intramolecular RNA-RNA interactions, which can conceal target sites for many minutes in the absence of translation. Our results uncover how dynamic changes in mRNA structure shape AGO2-target recognition, provide estimates of mRNA folding and unfolding rates in vivo, and provide experimental evidence for the role of mRNA structural dynamics in control of mRNA-protein interactions.

ObjectivesTo compare prevalence and severity of diaper dermatitis (DD) in infants and toddlers (babies) across three countries (China, USA, and Germany), including diapered skin measures and caregiver practices.MethodsA cross-sectional study of 1791 babies (~600 from each country) was recruited at each clinical site. Based on regional toilet-training habits, exclusively diaper-wearing infants were recruited between ages 2-8 months in China and 2-18 months in the USA and Germany. DD was measured, as well as skin pH, transepidermal water loss (TEWL), and relative humidity (RH) in the diapered region. Caregiver habits were collected via a questionnaire and included information on hygienic practices.ResultsDiaper dermatitis was highest in the perianal area, followed by the intertriginous, genital, and buttock regions. In general, DD was significantly lower in babies in China, highest in Germany, and intermediate in the USA. This rank ordering of DD by geography was also observed in baby age 2-8 months. The lower DD observed in China was associated with lower skin pH and TEWL on diapered skin and decreased RH in the diaper. Chinese caregivers had the highest rate of prophylactic topical product usage, the most robust cleaning of the diapered area, lack of cleansing after urine-only diaper changes, and Chinese infants spent the least time in an overnight diaper.ConclusionsThese data suggest caregiver behaviors including prophylactic use of topical products, thorough cleaning after stooling and reduced time in an overnight diaper are associated with less DD, lower superficial skin pH, and enhanced skin barrier.

Small interfering RNAs (siRNAs) promote RNA degradation in a variety of processes and have important clinical applications. siRNAs direct cleavage of target RNAs by guiding Argonaute2 (AGO2) to its target site. Target site accessibility is critical for AGO2-target interactions, but how target site accessibility is controlled in vivo is poorly understood. Here, we use live-cell single-molecule imaging in human cells to determine rate constants of the AGO2 cleavage cycle in vivo. We find that the rate-limiting step in mRNA cleavage frequently involves unmasking of target sites by translating ribosomes. Target site masking is caused by heterogeneous intramolecular RNA-RNA interactions, which can conceal target sites for many minutes in the absence of translation. Our results uncover how dynamic changes in mRNA structure shape AGO2-target recognition, provide estimates of mRNA folding and unfolding rates in vivo, and provide experimental evidence for the role of mRNA structural dynamics in control of mRNA-protein interactions.

This paper proposes a plane wave activation based neural network (PWNN) for solving Helmholtz equation, the basic partial differential equation to represent wave propagation, e.g. acoustic wave, electromagnetic wave, and seismic wave. Unlike using traditional activation based neural network (TANN) or $sin$ activation based neural network (SIREN) for solving general partial differential equations, we instead introduce a complex activation function $e^{\mathbf{i}{x}}$, the plane wave which is the basic component of the solution of Helmholtz equation. By a simple derivation, we further find that PWNN is actually a generalization of the plane wave partition of unity method (PWPUM) by additionally imposing a learned basis with both amplitude and direction to better characterize the potential solution. We firstly investigate our performance on a problem with the solution is an integral of the plane waves with all known directions. The experiments demonstrate that: PWNN works much better than TANN and SIREN on varying architectures or the number of training samples, that means the plane wave activation indeed helps to enhance the representation ability of neural network toward the solution of Helmholtz equation; PWNN has competitive performance than PWPUM, e.g. the same convergence order but less relative error. Furthermore, we focus a more practical problem, the solution of which only integrate the plane waves with some unknown directions. We find that PWNN works much better than PWPUM at this case. Unlike using the plane wave basis with fixed directions in PWPUM, PWNN can learn a group of optimized plane wave basis which can better predict the unknown directions of the solution. The proposed approach may provide some new insights in the aspect of applying deep learning in Helmholtz equation.

In recent studies, Generative Adversarial Network (GAN) is one of the popular schemes to augment the image dataset. However, in our study we find the generator G in the GAN fails to generate numerical data in lower-dimensional spaces, and we address overfitting in the generation. By analyzing the Directed Graphical Model (DGM), we propose a theoretical restraint, independence on the loss function, to suppress the overfitting. Practically, as the Statically Restrained GAN (SRGAN) and Dynamically Restrained GAN (DRGAN), two frameworks are proposed to employ the theoretical restraint to the network structure. In the static structure, we predefined a pair of particular network topologies of G and D as the restraint, and quantify such restraint by the interpretable metric Similarity of the Restraint (SR). While for DRGAN we design an adjustable dropout module for the restraint function. In the widely carried out 20 group experiments, on four public numerical class imbalance datasets and five classifiers, the static and dynamic methods together produce the best augmentation results of 19 from 20; and both two methods simultaneously generate 14 of 20 groups of the top-2 best, proving the effectiveness and feasibility of the theoretical restraints.

Super-resolution imaging allows for the visualization of cellular structures on a nanoscale level. DNA-PAINT (DNA point accumulation in nanoscale topology) is a super-resolution method that depends on the binding and unbinding of DNA imager strands. The current DNA-PAINT technique suffers from slow acquisition due to the low binding rate of the imager strands. Here we report on a method where imager strands are loaded into a protein, Argonaute (Ago), which allows for faster binding. Ago preorders the DNA imager strand into a helical conformation, allowing for 10 times faster target binding. Using a 2D DNA origami structure, we demonstrate that Ago-assisted DNA-PAINT (Ago-PAINT) can speed up the current DNA-PAINT technique by an order of magnitude, while maintaining the high spatial resolution. We envision this tool to be useful for super-resolution imaging and other techniques that rely on nucleic acid interactions.

Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n = 49) were classified into high- and low-HPV-titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA sequencing, and the results were validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPVs act as trigger of cancer development whereas somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins plays a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management., De 2 första författarna delar förstaförfattarskapet.

Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n=49) were classified into high and low HPV titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA-sequencing, and the results validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPV act as trigger of cancer development while somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins play a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.

Catchment-scale hydrological and hydrogeological investigations commonly conclude by finding that particular stream reaches are either gaining or losing; they also often assume that the influence of bedrock aquifers on catchment water balances and water quality is insignificant. However, in many cases, such broad findings are likely to oversimplify the spatial and temporal complexity of the connections between the different hydrological system components, particularly in regions dominated by cycles of droughts and flooding. From a modelling perspective, such oversimplifications can have serious implications on the process of identifying the magnitude and direction of the exchange fluxes between the surface and groundwater systems. In this study, we use 3D geological modelling and historic water chemistry and hydraulic records to identify the origins of groundwater at different locations in the alluvium and along the course of streams in the Lockyer Valley (Queensland, Australia), a catchment impacted by a severe drought (‘Millennium Drought’) from 1998 to 2009, followed by extensive flooding in 2011. We also demonstrate how discharge from the sub-alluvial regional-scale volcanic and sedimentary bedrock influences the water balance and water quality of the alluvium and streams. The investigation of aquifer geometry via development of a three-dimensional geological model combined with an assessment of hydraulic data provided important insights on groundwater flow paths and helped to identify areas where bedrock aquifers interact with shallow alluvial aquifers and streams. Multivariate statistical techniques were then applied as an additional line of evidence to groundwater and surface water hydrochemical data from large historical datasets. This confirmed that most sub-catchments within the Lockyer Valley have distinct water chemistry patterns, which result from mixing of different water sources, including discharge from the sub-alluvial bedrock. Importantly, in addit

Prokaryotic Argonaute proteins (pAgos) constitute a diverse group of endonucleases of which some mediate host defense by utilizing small interfering DNA guides (siDNA) to cleave complementary invading DNA. This activity can be repurposed for programmable DNA cleavage. However, currently characterized DNA-cleaving pAgos require elevated temperatures (≥65°C) for their activity, making them less suitable for applications that require moderate temperatures, such as genome editing. Here, we report the functional and structural characterization of the siDNA-guided DNA-targeting pAgo from the mesophilic bacterium Clostridium butyricum (CbAgo). CbAgo displays a preference for siDNAs that have a deoxyadenosine at the 5'-end and thymidines at nucleotides 2-4. Furthermore, CbAgo mediates DNA-guided DNA cleavage of AT-rich double stranded DNA at moderate temperatures (37°C). This study demonstrates that certain pAgos are capable of programmable DNA cleavage at moderate temperatures and thereby expands the scope of the potential pAgo-based applications.

Some recent studies have suggested using GANs for numeric data generation such as to generate data for completing the imbalanced numeric data. Considering the significant difference between the dimensions of the numeric data and images, as well as the strong correlations between features of numeric data, the conventional GANs normally face an overfitting problem, consequently leads to an ill-conditioning problem in generating numeric and structured data. This paper studies the constrained network structures between generator G and discriminator D in WGAN, designs several structures including isomorphic, mirror and self-symmetric structures. We evaluates the performances of the constrained WGANs in data augmentations, taking the non-constrained GANs and WGANs as the baselines. Experiments prove the constrained structures have been improved in 17/20 groups of experiments. In twenty experiments on four UCI Machine Learning Repository datasets, Australian Credit Approval data, German Credit data, Pima Indians Diabetes data and SPECT heart data facing five conventional classifiers. Especially, Isomorphic WGAN is the best in 15/20 experiments. Finally, we theoretically proves that the effectiveness of constrained structures by the directed graphic model (DGM) analysis.

Argonaute (Ago) proteins are key players in both gene regulation (eukaryotes) and host defense (prokaryotes). Acting on single-stranded nucleic-acid substrates, Ago relies on base pairing between a small nucleic-acid guide and its complementary target sequences for specificity. To efficiently scan nucleic-acid chains for targets, Ago diffuses laterally along the substrate and must bypass secondary structures as well as protein barriers. Using single-molecule FRET in conjunction with kinetic modelling, we reveal that target scanning is mediated through loose protein-nucleic acid interactions, allowing Ago to slide short distances over secondary structures, as well as to bypass protein barriers via intersegmental transfer. Our combined single-molecule experiment and kinetic modelling approach may serve as a platform to dissect search processes and study the effect of sequence on search kinetics for other nucleic acid-guided proteins.

Prokaryotic Argonaute proteins (pAgos) constitute a diverse group of endonucleases of which some mediate host defense by utilizing small interfering DNA guides (siDNA) to cleave complementary invading DNA. This activity can be repurposed for programmable DNA cleavage. However, currently characterized DNA-cleaving pAgos require elevated temperatures (≥65°C) for their activity, making them less suitable for applications that require moderate temperatures, such as genome editing. Here, we report the functional and structural characterization of the siDNA-guided DNA-targeting pAgo from the mesophilic bacterium Clostridium butyricum (CbAgo). CbAgo displays a preference for siDNAs that have a deoxyadenosine at the 5'-end and thymidines at nucleotides 2-4. Furthermore, CbAgo mediates DNA-guided DNA cleavage of AT-rich double stranded DNA at moderate temperatures (37°C). This study demonstrates that certain pAgos are capable of programmable DNA cleavage at moderate temperatures and thereby expands the scope of the potential pAgo-based applications.

Ning Li,1 Tao Cui,2 Wenling Guo,1 Dianwei Wang,1 Li Mao31Obstetrical Department, Binzhou Central Hospital, Binzhou, Shandong 251700, People’s Republic of China; 2Anesthesiology Department, Huimin County Maternal and Child Health Hospital, Binzhou, Shandong, 251700, People’s Republic of China; 3Gynecology Department, Binzhou Central Hospital, Binzhou, Shandong 251700, People’s Republic of ChinaBackground: The dysregulation of microRNAs has been implicated in the progression of different malignancies. Herein, we sought to identify the precise roles of miR-155-5p in the progression of cervical cancer.Materials and methods: The expressions of miR-155-5p in cervical carcinoma cells and clinical tissues were assessed using qRT-PCR analysis. The functions of miR-155-5p on the growth of cervical cancer cell were investigated using MTT and colony formation. The Transwell and wound closure assays were selected to explore the influence of miR-155-5p on the invasion and migration of cervical cancer cell. The effect of miR-155-5p on cervical carcinoma cell growth and metastasis in vivo was investigated using xenograft model and experimental lung metastasis model. Bioinformatics analysis and luciferase reporter assay were applied to identify that tumor protein p53-inducible nuclear protein 1 (TP53INP1) was the target of miR-155-5p.Results: MiR-155-5p was significantly upregulated in cervical cancer tissue than that in control normal tissue. Downexpression of miR-155-5p decreased the growth, migration as well as invasiveness abilities of cervical cancer cell in vitro whereas overregulation of miR-155-5p caused the opposite outcomes. In addition, the in vivo mice xenograft model suggested that downexpression of miR-155-5p restrained the progression of cervical cancer cell whereas overexpression of miR-155-5p caused opposite outcomes. Furthermore, we revealed that TP53INP1 was the target of miR-155-5p and the level of TP53INP1 was inversely associated w

He-Lin Xu,1,* Fu-Rong Tian,1,* Jian Xiao,1,* Pian-Pian Chen,1 Jie Xu,1 Zi-Liang Fan,1 Jing-Jing Yang,1 Cui-Tao Lu,1 Ying-Zheng Zhao1,2 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 2Hainan Medical College, Haikou, China *These authors contributed equally to this work Introduction: The short lifetime of protein-based therapies has largely limited their therapeutic efficacy in injured nervous post-spinal cord injury (post-SCI). Methods: In this study, an affinity-based hydrogel delivery system provided sustained-release of proteins, thereby extending the efficacy of such therapies. The affinity-based hydrogel was constructed using a novel polymer, heparin-poloxamer (HP), as a temperature-sensitive bulk matrix and decellular spinal cord extracellular matrix (dscECM) as an affinity depot of drug. By tuning the concentration of HP in formulation, the cold ternary fibroblast growth factor-2 (FGF2)-dscECM-HP solution could rapidly gelatinize into a hydrogel at body temperature. Due to the strong affinity for FGF2, hybrid FGF2-dscECM-HP hydrogel enabled sustained-release of encapsulated FGF2 over an extended period in vitro. Results: Compared to free FGF2, it was observed that both neuron functions and tissue morphology after SCI were clearly recovered in rats treated with FGF2-dscECM-HP hydrogel. Moreover, the expression of neurofilament protein and the density of axons were increased after treatment with hybrid FGF2-dscECM-HP. In addition, the neuroprotective effects of FGF2-dscECM-HP were related to inhibition of chronic endoplasmic reticulum stress-induced apoptosis.Conclusion: The results revealed that a hybrid hydrogel system may be a potential carrier to deliver macromolecular proteins to the injured site and enhance the therapeutic effects of proteins.Keywords: spinal cord injury, decellularized extracellular matrix, thermosensitive hydrogel, adsorption, basic fibroblast growth factor

He-Lin Xu,1,* Fu-Rong Tian,1,* Jian Xiao,1,* Pian-Pian Chen,1 Jie Xu,1 Zi-Liang Fan,1 Jing-Jing Yang,1 Cui-Tao Lu,1 Ying-Zheng Zhao1,2 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 2Hainan Medical College, Haikou, China *These authors contributed equally to this work Introduction: The short lifetime of protein-based therapies has largely limited their therapeutic efficacy in injured nervous post-spinal cord injury (post-SCI). Methods: In this study, an affinity-based hydrogel delivery system provided sustained-release of proteins, thereby extending the efficacy of such therapies. The affinity-based hydrogel was constructed using a novel polymer, heparin-poloxamer (HP), as a temperature-sensitive bulk matrix and decellular spinal cord extracellular matrix (dscECM) as an affinity depot of drug. By tuning the concentration of HP in formulation, the cold ternary fibroblast growth factor-2 (FGF2)-dscECM-HP solution could rapidly gelatinize into a hydrogel at body temperature. Due to the strong affinity for FGF2, hybrid FGF2-dscECM-HP hydrogel enabled sustained-release of encapsulated FGF2 over an extended period in vitro. Results: Compared to free FGF2, it was observed that both neuron functions and tissue morphology after SCI were clearly recovered in rats treated with FGF2-dscECM-HP hydrogel. Moreover, the expression of neurofilament protein and the density of axons were increased after treatment with hybrid FGF2-dscECM-HP. In addition, the neuroprotective effects of FGF2-dscECM-HP were related to inhibition of chronic endoplasmic reticulum stress-induced apoptosis.Conclusion: The results revealed that a hybrid hydrogel system may be a potential carrier to deliver macromolecular proteins to the injured site and enhance the therapeutic effects of proteins.Keywords: spinal cord injury, decellularized extracellular matrix, thermosensitive hydrogel, adsorption, basic fibroblast growth factor

Background Genetic variants within the fatty acid desaturase (FADS) gene cluster (human Chr11) are important regulators of long-chain (LC) polyunsaturated fatty acid (PUFA) biosynthesis in the liver and consequently have been associated with circulating LC-PUFA levels. More recently, epigenetic modifications such as DNA methylation, particularly within the FADS cluster, have been shown to affect LC-PUFA levels. Our lab previously demonstrated strong associations of allele-specific methylation (ASM) between a single nucleotide polymorphism (SNP) rs174537 and CpG sites across the FADS region in human liver tissues. Given that epigenetic signatures are tissue-specific, we aimed to evaluate the methylation status and ASM associations between rs174537 and DNA methylation obtained from human saliva, CD4+ cells and total leukocytes derived from whole blood. The goals were to (1) determine if DNA methylation from these peripheral samples would display similar ASM trends as previously observed in human liver tissues and (2) evaluate the associations between DNA methylation and circulating LC-PUFAs. Results DNA methylation at six CpG sites spanning FADS1 and FADS2 promoter regions and a putative FADS enhancer region were determined in two Caucasian cohorts of healthy volunteers: leukocytes in cohort 1 (n = 89, median age = 43, 35% male) and saliva and CD4+ cells in cohort 2 (n = 32, median age = 41, 41% male). Significant ASM between rs174537 and DNA methylation at three CpG sites located in the FADS2 promoter region (i.e., chr11:61594865, chr11:61594876, chr11:61594907) and one CpG site in the putative enhancer region (chr11:61587979) were observed with leukocytes. In CD4+ cells, significant ASM was observed at CpG sites chr11:61594876 and chr11:61584894. Genotype at rs174537 was significantly associated with DNA methylation from leukocytes. Similar trends were observed with CD4+ cells, but not with saliva. DNA methylation from leukocytes and CD4+ cells also significantly co

Polymer flooding is a mature enhanced oil recovery technique that has been successfully applied in many field projects. By injecting polymer into a reservoir, the viscosity of water is increased, and the efficiency of water flooding is improved. As a result, more oil can be recovered. This paper presents numerical simulations of a polymer flooding process using parallel computers, where the numerical modeling of polymer retention, inaccessible pore volumes, a permeability reduction and polymer absorption are considered. Darcy's law is employed to model the behavoir of a fluid in porous media, and the upstream finite difference (volume) method is applied to discretize the mass conservation equations. Numerical methods, including discretization schemes, linear solver methods, nonlinearization methods and parallel techniques are introduced. Numerical experiments show that, on one hand, computed results match those from the commercial simulator, Schlumberger-Eclipse, which is widely applied by the petroleum industry, and, on the other hand, our simulator has excellent scalability, which is demonstrated by field applications with up to 27 million grid blocks using up to 2048 CPU cores.

The two-phase oil-water flow in natural fractured reservoirs and its numerical methods are introduced in this paper, where the fracture is modeled by the dual porosity method. Efficient numerical method, including the finite difference method, CPR-FPF preconditioners for linear systems and effective decoupling method, are presented. Parallel computing techniques employed in simulation are also presented. Using those numerical methods and parallel techniques, a parallel reservoir simulator is developed, which is capable of simulating large-scale reservoir models. The numerical results show that our simulator is accurate and scalable compared to the commercial software, and the numerical methods are also effective.

In recent years, high performance scientific computing on graphics processing units (GPUs) have gained widespread acceptance. These devices are designed to offer massively parallel threads for running code with general purpose. There are many researches focus on finite element method with GPUs. However, most of the works are specific to certain problems and applications. Some works propose methods for finite element assembly that is general for a wide range of finite element models. But the development of finite element code is dependent on the hardware architectures. It is usually complicated and error prone using the libraries provided by the hardware vendors. In this paper, we present architecture and implementation of finite element assembly for partial differential equations (PDEs) based on symbolic computation and runtime compilation technique on GPU. User friendly programming interface with symbolic computation is provided. At the same time, high computational efficiency is achieved by using runtime compilation technique. As far as we know, it is the first work using this technique to accelerate finite element assembly for solving PDEs. Experiments show that a one to two orders of speedup is achieved for the problems studied in the paper., Comment: 6 pages, 8 figures, conference

Xin-Qiao Tian,1,2,* Xian-Wei Ni,3,* He-Lin Xu,2,* Lei Zheng,4 De-Li ZhuGe,2 Bin Chen,4 Cui-Tao Lu,2 Jian-Jun Yuan,1 Ying-Zheng Zhao2 1Department of Ultrasonography, Henan Provincial People’s Hospital (People’s Hospital of Zhengzhou University), Zhengzhou, 2Department of Pharmacology, College of Pharmaceutical Sciences, Wenzhou Medical University, 3Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, 4Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China *These authors contributed equally to this work Abstract: The present study seeks to observe the preventive effects of doxorubicin-induced cardiomyopathy (DOX-CM) in rats using targeted non-mitogenic acidic fibroblast growth factor (MaFGF) mediated by nanoparticles (NP) combined with ultrasound-targeted MB destruction (UTMD). DOX-CM rats were induced by intraperitoneally injected doxorubicin. Six weeks after intervention, the indices from the transthoracic echocardiography and velocity vector imaging showed that the left ventricular function in the MaFGF-loaded NP (MaFGF-NP) + UTMD group was significantly improved compared with the DOX-CM group. The increased malondialdehyde and decreased superoxide dismutase were observed in the DOX-CM group, while a significant increase in superoxide dismutase and a decrease in malondialdehyde were detected in the groups treated with MaFGF-NP + UTMD. From the Masson staining, the MaFGF-NP + UTMD group showed a significant difference from the DOX-CM group. The cardiac collagen volume fraction and the ratio of the perivascular collagen area to the luminal area number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling positive cells in the MaFGF-NP + UTMD group decreased to 8.9%, 0.55-fold, compared with the DOX-CM group (26.5%, 1.7-fold). From terminal deoxynucleotidyl transferase-med

Si-Si Zhang,1,* Wei-Ting Xia,1,* Jie Xu,2 He-Lin Xu,2 Cui-Tao Lu,2 Ying-Zheng Zhao,2,* Xue-Qing Wu1,* 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang, People’s Republic of China *These authors contributed equally to this work Abstract: Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E2) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat’s endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E2-HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E2-HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E2-HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E2-HP hydrogel showed a prolonged release of E2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E2-HP hydrogel

Xin-Qiao Tian,1,2,* Xian-Wei Ni,3,* He-Lin Xu,2,* Lei Zheng,4 De-Li ZhuGe,2 Bin Chen,4 Cui-Tao Lu,2 Jian-Jun Yuan,1 Ying-Zheng Zhao2 1Department of Ultrasonography, Henan Provincial People’s Hospital (People’s Hospital of Zhengzhou University), Zhengzhou, 2Department of Pharmacology, College of Pharmaceutical Sciences, Wenzhou Medical University, 3Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, 4Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China *These authors contributed equally to this work Abstract: The present study seeks to observe the preventive effects of doxorubicin-induced cardiomyopathy (DOX-CM) in rats using targeted non-mitogenic acidic fibroblast growth factor (MaFGF) mediated by nanoparticles (NP) combined with ultrasound-targeted MB destruction (UTMD). DOX-CM rats were induced by intraperitoneally injected doxorubicin. Six weeks after intervention, the indices from the transthoracic echocardiography and velocity vector imaging showed that the left ventricular function in the MaFGF-loaded NP (MaFGF-NP) + UTMD group was significantly improved compared with the DOX-CM group. The increased malondialdehyde and decreased superoxide dismutase were observed in the DOX-CM group, while a significant increase in superoxide dismutase and a decrease in malondialdehyde were detected in the groups treated with MaFGF-NP + UTMD. From the Masson staining, the MaFGF-NP + UTMD group showed a significant difference from the DOX-CM group. The cardiac collagen volume fraction and the ratio of the perivascular collagen area to the luminal area number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling positive cells in the MaFGF-NP + UTMD group decreased to 8.9%, 0.55-fold, compared with the DOX-CM group (26.5%, 1.7-fold). From terminal deoxynucleotidyl transferase-med

Si-Si Zhang,1,* Wei-Ting Xia,1,* Jie Xu,2 He-Lin Xu,2 Cui-Tao Lu,2 Ying-Zheng Zhao,2,* Xue-Qing Wu1,* 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang, People’s Republic of China *These authors contributed equally to this work Abstract: Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E2) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat’s endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E2-HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E2-HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E2-HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E2-HP hydrogel showed a prolonged release of E2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E2-HP hydrogel

In this paper a new hp-adaptive strategy for elliptic problems based on refinement history is proposed, which chooses h-, p- or hp-refinement on individual elements according to a posteriori error estimate, as well as smoothness estimate of the solution obtained by comparing the actual and expected error reduction rate. Numerical experiments show that exponential convergence can be achieved with this strategy.

For the parallel computation of partial differential equations, one key is the grid partitioning. It requires that each process owns the same amount of computations, and also, the partitioning quality should be proper to reduce the communications among processes. When calculating the partial differential equations using adaptive finite element methods, the grid and the basis functions adjust in each iteration, which introduce load balancing issues. The grid should be redistributed dynamically. This paper studies dynamic load balancing algorithms and the implementation on the adaptive finite element platform PHG. The numerical experiments show that algorithms studied in this paper have good partitioning quality, and they are efficient., Comment: in Chinese

In the first part of this thesis, we exploit wireless broadcast across different layers in wireless networks. The wireless channel is distinguished by its broadcast nature. Wireless broadcast provides a fertile ground to improve the efficiency of existing wireless networks and design new ones. Specifically, we first consider relaying strategies for memoryless two-way relay channels at the physical layer. We generalize networking layer network coding operating on a finite field to physical layer network coding, which is a mapping from the relay's received signal to its transmitted signal. We analyze the symbol-error performance of several relay strategies, and optimize the relay function via functional analysis. Our results indicate that the interference caused by wireless broadcast can be exploited to improve the spectrum efficiency. We then develop a cross-layer framework with wireless broadcast, which integrates rate control, network coding and scheduling in transport, network and link layers. Under the primary interference model, we show that the link scheduling problem is the maximum weighted hypergraph matching problem, which is NP-complete. We propose several distributed approximation algorithms and bound their worst case performance. Next, we describe a new class of medium access control (MAC) protocol, which uses successive interference cancelation to resolve packet collision due to wireless broadcast. Each user is allowed to transmit at different data rates chosen randomly from an appropriately determined set of rates. We characterize the throughput of the proposed protocol compared to that with a centralized controller. A game-theoretic framework along with the dynamic algorithms is proposed to achieve the desired throughput optimal equilibrium, which provides a valuable perspective to understand existing MAC protocols and a general framework to design new ones to improve the system performance. In the second part of this the

In the first part of this thesis, we exploit wireless broadcast across different layers in wireless networks. The wireless channel is distinguished by its broadcast nature. Wireless broadcast provides a fertile ground to improve the efficiency of existing wireless networks and design new ones. Specifically, we first consider relaying strategies for memoryless two-way relay channels at the physical layer. We generalize networking layer network coding operating on a finite field to physical layer network coding, which is a mapping from the relay's received signal to its transmitted signal. We analyze the symbol-error performance of several relay strategies, and optimize the relay function via functional analysis. Our results indicate that the interference caused by wireless broadcast can be exploited to improve the spectrum efficiency. We then develop a cross-layer framework with wireless broadcast, which integrates rate control, network coding and scheduling in transport, network and link layers. Under the primary interference model, we show that the link scheduling problem is the maximum weighted hypergraph matching problem, which is NP-complete. We propose several distributed approximation algorithms and bound their worst case performance. Next, we describe a new class of medium access control (MAC) protocol, which uses successive interference cancelation to resolve packet collision due to wireless broadcast. Each user is allowed to transmit at different data rates chosen randomly from an appropriately determined set of rates. We characterize the throughput of the proposed protocol compared to that with a centralized controller. A game-theoretic framework along with the dynamic algorithms is proposed to achieve the desired throughput optimal equilibrium, which provides a valuable perspective to understand existing MAC protocols and a general framework to design new ones to improve the system performance. In the second part of this the

In the first part of this thesis, we exploit wireless broadcast across different layers in wireless networks. The wireless channel is distinguished by its broadcast nature. Wireless broadcast provides a fertile ground to improve the efficiency of existing wireless networks and design new ones. Specifically, we first consider relaying strategies for memoryless two-way relay channels at the physical layer. We generalize networking layer network coding operating on a finite field to physical layer network coding, which is a mapping from the relay's received signal to its transmitted signal. We analyze the symbol-error performance of several relay strategies, and optimize the relay function via functional analysis. Our results indicate that the interference caused by wireless broadcast can be exploited to improve the spectrum efficiency. We then develop a cross-layer framework with wireless broadcast, which integrates rate control, network coding and scheduling in transport, network and link layers. Under the primary interference model, we show that the link scheduling problem is the maximum weighted hypergraph matching problem, which is NP-complete. We propose several distributed approximation algorithms and bound their worst case performance. Next, we describe a new class of medium access control (MAC) protocol, which uses successive interference cancelation to resolve packet collision due to wireless broadcast. Each user is allowed to transmit at different data rates chosen randomly from an appropriately determined set of rates. We characterize the throughput of the proposed protocol compared to that with a centralized controller. A game-theoretic framework along with the dynamic algorithms is proposed to achieve the desired throughput optimal equilibrium, which provides a valuable perspective to understand existing MAC protocols and a general framework to design new ones to improve the system performance. In the second part of this the

Ying-Zheng Zhao,1,2 Ming Zhang,1 Xin-Qiao Tian,3 Lei Zheng,4 Cui-Tao Lu1,2 1College of Pharmaceutical Sciences, Wenzhou Medical University, 2Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 3Department of Ultrasonic Diagnosis, Henan Provincial People’s Hospital, Zhengzhou City, Henan, 4Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Abstract: Basic fibroblast growth factor (bFGF)-loaded liposome (bFGF-lip) combined with ultrasound-targeted microbubble destruction (UTMD) technique was investigated to prevent diabetic cardiomyopathy (DCM). Cardiac function and myocardial ultrastructure were assessed. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, immunohistochemistry staining, and Western blot assay were used to investigate the signal pathway underlying the expression of bFGF in DCM treatment. From Mason staining and TUNEL staining, bFGF-lip + UTMD group showed significant differences from the diabetes group and other groups treated with bFGF or bFGF-lip. The diabetes group showed similar results (myocardial capillary density, collagen volume fraction, and cardiac myocyte apoptosis index) to other bFGF treatment groups. Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis, and metabolic disturbances could be suppressed by the different extents of twice-weekly bFGF treatments for 12 consecutive weeks (free bFGF or bFGF-lip +/- UTMD), with the strongest improvements observed in the bFGF-lip + UTMD group. The group combining bFGF-lip with UTMD demonstrated the highest level of bFGF expression among all the groups. The bFGF activated the PI3K/AKT signal pathway, causing the reduction of myocardial cell apop

Ying-Zheng Zhao,1,2 Ming Zhang,1 Xin-Qiao Tian,3 Lei Zheng,4 Cui-Tao Lu1,2 1College of Pharmaceutical Sciences, Wenzhou Medical University, 2Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 3Department of Ultrasonic Diagnosis, Henan Provincial People’s Hospital, Zhengzhou City, Henan, 4Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Abstract: Basic fibroblast growth factor (bFGF)-loaded liposome (bFGF-lip) combined with ultrasound-targeted microbubble destruction (UTMD) technique was investigated to prevent diabetic cardiomyopathy (DCM). Cardiac function and myocardial ultrastructure were assessed. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, immunohistochemistry staining, and Western blot assay were used to investigate the signal pathway underlying the expression of bFGF in DCM treatment. From Mason staining and TUNEL staining, bFGF-lip + UTMD group showed significant differences from the diabetes group and other groups treated with bFGF or bFGF-lip. The diabetes group showed similar results (myocardial capillary density, collagen volume fraction, and cardiac myocyte apoptosis index) to other bFGF treatment groups. Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis, and metabolic disturbances could be suppressed by the different extents of twice-weekly bFGF treatments for 12 consecutive weeks (free bFGF or bFGF-lip +/- UTMD), with the strongest improvements observed in the bFGF-lip + UTMD group. The group combining bFGF-lip with UTMD demonstrated the highest level of bFGF expression among all the groups. The bFGF activated the PI3K/AKT signal pathway, causing the reduction of myocardial cell apop

Hilbert order is widely applied in many areas. However, most of the algorithms are confined to low dimensional cases. In this paper, algorithms for encoding and decoding arbitrary dimensional Hilbert order are presented. Eight algorithms are proposed. Four algorithms are based on arithmetic operations and the other four algorithms are based on bit operations. For the algorithms complexities, four of them are linear and the other four are constant for given inputs. In the end of the paper, algorithms for two dimensional Hilbert order are presented to demonstrate the usage of the algorithms introduced.

Juntao Feng,1 Jinhai Gou,1 Jia Jia,1 Tao Yi,2 Tao Cui,1 Zhengyu Li1,2 1Department of Gynecology and Obstetrics, 2Sichuan Key Laboratory of Gynecologic Oncology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP–TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP–TEAD complex. Keywords: YAP, CCN2, ovarian cancer, verteporfin, Hippo pathway

The genetic architecture of susceptibility to cervical cancer is not well-understood. By using a genome-wide association study (GWAS) of 1034 cervical cancer patients and 3948 controls with 632 668 single-nucleotide polymorphisms (SNPs), we estimated that 24.0% [standard error (SE) = 5.9%, P = 3.19 x 10(-6)] of variation in liability to cervical cancer is captured by autosomal SNPs, a bit lower than the heritability estimated from family study (27.0%), suggesting that a substantial proportion of the heritability is tagged by common SNPs. The remaining missing heritability most probably reflects incomplete linkage disequilibrium between causal variants and the genotyped SNPs. The variance explained by each chromosome is not related to its length (R-2 = 0.020, P = 0.516). Published genome-wide significant variants only explain 2.1% (SE = 1.5%, P = 0) of phenotypic variance, which reveals that most of the heritability has not been detected, presumably due to small individual effects. Another 2.1% (SE = 1.1%, P = 0.013) of variation is attributable to biological pathways associated with risk of cervical cancer, supporting that pathway analysis can identify part of the hidden heritability. Except for human leukocyte antigen genes and MHC class I polypeptide-related sequence A (MICA), none of the 82 candidate genes/regions reported in other association studies contributes to the heritability of cervical cancer in our dataset. This study shows that risk of cervical cancer is influenced by many common germline genetic variants of small effects. The findings are important for further study design to identify the hiding heritability that has not yet been revealed. More susceptibility loci are yet to be found in GWASs with higher power.

Cui-Tao Lu,1,2 Rong-Rong Jin,2 Yi-Na Jiang,2 Qian Lin,2 Wen-Zhe Yu,2 Kai-Li Mao,2 Fu-Rong Tian,2 Ya-Ping Zhao,1,* Ying-Zheng Zhao2,* 1The Second Affiliated Hospital, Wenzhou Medical University, 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China *These authors contributed equally to this work Background: The aim of this study was to investigate the protective role of intranasally administered substance P-loaded gelatin nanoparticles (SP-GNPs) against 6-hydroxydopamine (6-OHDA)-induced apoptosis in vitro and in vivo, and to provide a new strategy for treating brain pathology, such as Parkinson’s disease.Methods: SP-GNPs were prepared by a water-in-water emulsion method, and their stability, encapsulating efficiency, and loading capacity were evaluated. PC-12 cells were used to examine the enhancement of growth and inhibition of apoptosis by SP-GNPs in vitro using MTT assays. In the in vivo study, hemiparkinsonian rats were created by intracerebroventricular injection of 6-OHDA. The rats then received intranasal SP-GNPs daily for 2 weeks. Functional improvement was assessed by quantifying rotational behavior, and the degree of apoptosis was assessed by immunohistochemical staining for caspase-3 in the substantia nigra region.Results: PC-12 cells with 6-OHDA-induced disease treated with SP-GNPs showed higher cell viability than their untreated counterparts, and cell viability increased as the concentration of substance P (SP) increased, indicating that SP could enhance cell growth and inhibit the cell apoptosis induced by 6-OHDA. Rats with 6-OHDA-induced hemiparkinsonism treated with SP-GNPs made fewer rotations and showed less staining for caspase-3 than their counterparts not treated with SP, indicating that SP protects rats with 6-OHDA-induced hemiparkinsonism from apoptosis and therefore demonstrates their functional improvement.Conclusion: Intranasal delivery of SP-GNPs protects against 6

A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we re-examined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product (ARTP) test in a genome-wide association study of 1,034 cervical cancer patients and 3,948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal p-value < 0.05 (Tumor necrosis factor [TNF], p = 5.0×10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], p = 2.2×10(-3); Exonuclease 1 [EXO1], p=4.7×10(-3); Excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], p = 0.020; Transmembrane channel-like 6 and 8 genes [TMC6-TMC8], p = 0.023; Secreted phosphoprotein 1 [SPP1], p= 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], p = 0.033 and Chloride channel, voltage-sensitive 7 [CLCN7], p = 0.047). After correction for multiple testing only TNF remained statistically significant (p = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (LD) (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.

Cui-Tao Lu,1 Ying-Zheng Zhao,2,3 Ho Lun Wong,4 Jun Cai,5 Lei Peng,2 Xin-Qiao Tian1 1The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 2Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China; 3College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China; 4School of Pharmacy, Temple University, Philadelphia, PA, USA; 5Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA Abstract: Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. Keywords: drug delivery system, blood–brain barrier (BBB), central nervous system, brain-targeted therapy, cerebrospinal fluid (CSF)A Letter to the editor has been published about this paper

Cui-Tao Lu,1 Ying-Zheng Zhao,2,3 Ho Lun Wong,4 Jun Cai,5 Lei Peng,2 Xin-Qiao Tian1 1The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 2Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China; 3College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China; 4School of Pharmacy, Temple University, Philadelphia, PA, USA; 5Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA Abstract: Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. Keywords: drug delivery system, blood–brain barrier (BBB), central nervous system, brain-targeted therapy, cerebrospinal fluid (CSF)A Letter to the editor has been published about this paper

Background Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required. Materials and methods Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases. Results A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification. Conclusions We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.

Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors., De två första författarna delar första författarskapet.