bluuebunny/crossref_metadata_2025 huggingface dataset:
Data-Driven Modelling of Smart Building Ventilation Subsystem
Authors: Stamatescu Grigore , Stamatescu Iulia , Arghira Nicoleta , Fagarasan Ioana
Published: March 2019

Considering the advances in building monitoring and control through networks of interconnected devices, effective handling of the associated rich data streams is becoming an important challenge. In many situations, the application of conventional system identification or approximate grey-box models, partly theoretic and partly data driven, is either unfeasible or unsuitable. The paper discusses and illustrates an application of black-box modelling achieved using data mining techniques with the purpose of smart building ventilation subsystem control. We present the implementation and evaluation of a data mining methodology on collected data from over one year of operation. The case study is carried out on four air handling units of a modern campus building for preliminary decision support for facility managers. The data processing and learning framework is based on two steps: raw data streams are compressed using the Symbolic Aggregate Approximation method, followed by the resulting segments being input into a Support Vector Machine algorithm. The results are useful for deriving the behaviour of each equipment in various modi of operation and can be built upon for fault detection or energy efficiency applications. Challenges related to online operation within a commercial Building Management System are also discussed as the approach shows promise for deployment.
The Effect of Taxifolin on Cisplatin-Induced Pulmonary Damage in Rats: A Biochemical and Histopathological Evaluation
Authors: Unver Edhem , Tosun Mustafa , Olmez Hasan , Kuzucu Mehmet , Cimen Ferda Keskin , Suleyman Zeynep
Published: March 2019

The effect of taxifolin on cisplatin-induced oxidative pulmonary damage was investigated biochemically and histopathologically in male albino Wistar rats. There were four groups, with six animals in each group: 50 mg/kg of taxifolin plus 2.5 mg/kg of cisplatin (TC) group, 2.5 mg/kg of cisplatin only (CIS) group, 50 mg/kg of taxifolin only (TG) group, and a healthy control group (HG). In terms of the experimental procedure, the animals in the TC and TG groups were first treated via oral gavage. The CIS and HG groups received distilled water as solvent, respectively. One hour later, the TC and CIS groups received cisplatin at a dose of 2.5 mg/kg (injected intraperitoneally). Taxifolin, cisplatin, and the distilled water were administered at the indicated dose and volume, using the same method daily for 14 d. At the end of this period, the animals were killed with a high dosage of thiopental anaesthesia (50 mg/kg). Blood and lung tissue samples were taken for biochemical (malondialdehyde (MDA), myeloperoxidase (MPO), total glutathione (tGSH), and 8-hydroxy-2 deoxyguanosine (8-OHdG)) analyses and histopathological examinations. The biochemical and histopathological results in the TC and HG groups were then compared with those in the CIS group. Cisplatin increased the levels of MDA, myeloperoxidase, and 8-OHdG, a marker of oxidative DNA damage, and reduced the amount of tGSH in the lung tissue. Moreover, severe alveolar damage, including oedema and extensive alveolar septal fibrosis, in addition to infiltration of polymorphic nuclear leucocytes and haemorrhagic foci, was observed in the CIS group. These histopathological findings demonstrate that taxifolin provides protection against pulmonary oxidative stress by preventing increases in oxidant parameters and decreases in antioxidants.
Mathematical Strategies for Design Optimization of Multiphase Materials
Authors: Catania Rick , Diraz Abdalla , Maier Dominic , Tagle Armani , Acar Pınar
Published: March 2019

This work addresses various mathematical solution strategies adapted for design optimization of multiphase materials. The goal is to improve the structural performance by optimizing the distribution of multiple phases that constitute the material. Examples include the optimization of multiphase materials and composites with spatially varying fiber paths using a finite element analysis scheme. In the first application, the phase distribution of a two‐phase material is optimized to improve the structural performance. A radial basis function (RBF) based machine learning algorithm is utilized to perform a computationally efficient design optimization and it is found to provide equivalent results with the physical model. The second application concentrates on the optimization of spatially varying fiber paths of a composite material. The fiber paths are described by the Non‐Uniform Rational Bezier (B)‐Spline Surface (NURBS) using a bidirectional control point representation including 25 parameters. The optimum fiber path is obtained for various loading configurations by optimizing the NURBS parameters that control the overall distribution of fibers. Next, a direct sensitivity analysis is conducted to choose the critical set of parameters from the design point to improve the computational time efficiency. The optimized fiber path obtained with the reduced number of NURBS parameters is found to provide similar structural properties compared to the optimized fiber path that is modeled with a full NURBS representation with 25 parameters.
Effect of Long‐Wavelength Track Irregularities on Vehicle Dynamic Responses
Authors: Xin Tao , Wang Pengsong , Ding Yu
Published: March 2019

Long‐wavelength track irregularities have obvious influence on ride comfort and running stability of high‐speed trains. Meanwhile, it brings risk to the inspection of track irregularities since ordinary inspection equipment has difficulties in covering long wavelengths. Previous research on the effect of long‐wavelength track irregularities is rare. In order to find the relationship between long‐wavelength irregularities and vehicle dynamic responses, a numerical vehicle‐track coupling dynamic model based on multibody dynamics and finite element theories is established by using a self‐compiling program. One case study is given as an example to show the methodology of determining the sensitive long wavelength and management amplitude of track longitudinal‐level irregularities in high‐speed railway. The simulation results show that the sensitive long wavelength has a strong correlation with train speed and natural frequency. The simulation and field test results are in good agreement.
Potential Regulatory Effects of miR-182-3p in Osteosarcoma via Targeting EBF2
Authors: Chen Gaoyang , Yu Wenqing , Li Zhaoyan , Wang Qingyu , Yang Qiwei , Du Zhenwu , Zhang Guizhen , Song Yang
Published: March 2019

Osteosarcoma (OS) is one of the most common primary malignant bone tumors in adolescents with a high mortality rate. MicroRNA (miRNA) is a kind of noncoding RNAs and has been proved to participate in many physiological processes. Many miRNAs have been reported to act as function regulators in OS. In our study, the miRNA and gene expression profiles of OS were downloaded from GEO Datasets and the differential expression analysis was performed using GEO2R. 58 up- and 126 downregulated miRNAs were found. In the three OS gene profiles, 125 up- and 27 downregulated genes were found to be differentially expressed in at least two profiles. The miRNA-mRNA networks were constructed to predict the potential target genes of 10 most up- and downregulated miRNA. Venn analysis was used to detect the coexpressed differentially expressed genes (DEGs). EBF2, one of the upregulated DEGs, was also a potential target gene of miR-182-3p. Knockdown and overexpression of miR-182-3p resulted in overexpression and downexpression of EBF2 separately. Luciferase reporter gene experiment further verified the binding site of miR-182-3p and EBF2. CCK8 assay showed that miR-182-3p knockdown can further enhance the proliferation activity of OS cells, while overexpressing miR-182-3p can inhibit the proliferation activity of OS cells. Our research indicated that downexpression of miR-182-3p in OS cells results in overexpression of EBF2 and promotes the progression of OS.
Physical and Chemical Modifications of Plant Fibres for Reinforcement in Cementitious Composites
Authors: Ahmad R. , Hamid R. , Osman S. A.
Published: March 2019

This paper highlights the physical and chemical surface modifications of plant fibre (PF) for attaining suitable properties as reinforcements in cementitious composites. Untreated PF faces insufficient adhesion between the fibres and matrix due to high levels of moisture absorption and poor wettability. These conditions accelerate degradation of the fibre in the composite. It is also essential to reduce the risk of hydrophilic PF conditions with surface modification, to enhance the mechanical properties of the fibres. Fibres that undergo chemical and physical modifications had been proven to exhibit improved fibre‐matrix interfacial adhesion in the composite and contribute to better composite mechanical properties. This paper also gives some recommendations for future research on chemical and physical modifications of PF.
Evaluation Method for the Liquefaction Potential Using the Standard Penetration Test Value Based on the CPTU Soil Behavior Type Index
Authors: Du Guangyin , Gao Changhui , Liu Songyu , Guo Qian , Luo Tao
Published: March 2019

Taking the project of the Su‐xin highway treated by using the resonant compaction method as the reference, a new method for the evaluation of liquefaction potential is proposed based on the piezocone penetration test (CPTU) and the standard penetration test (SPT). The soil behavior type index (Ic) obtained from CPTUs and the standard penetration test index (N63.5), obtained from SPTs, are analyzed for saturated silty sand and silt. The analysis result reveals a linear relationship between N63.5 and Ic, given by N63.5 = −18.8Ic + 52.0. The larger the value of Ic is, the greater the viscosity of soil is, and the smaller the value of N63.5 is. According to the method, liquefaction assessment of saturated silty sand and silt foundation can be conducted by using N63.5 based on the Code of Seismic Design of Building. N63.5 is expressed by a single Ic, which is calculated from the CPTU data. Compared with existing evaluation methods, this method can provide continuous standard penetration test values, moreover, this method involves a simple calculation, and the results obtained using the method are reliable.
Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women
Authors: Branavan Umayal , Muneeswaran Kajan , Wijesundera W. S. S. , Senanayake Anoma , Chandrasekharan N. Vishvanath , Wijeyaratne Chandrika N.
Published: March 2019

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Its aetiology, though yet unclear, is presumed to have an oligogenic basis interacting with environmental factors. Kisspeptins are peptide products of Kiss1 gene that control the hypothalamic pituitary (HPG) axis by acting via G protein-coupled receptor known as GPR54. There is paucity of data on the role of Kiss1 and GPR54 gene in PCOS. We aimed to identify the polymorphisms in Kiss1 and GPR54 genes and explore their association with serum kisspeptin levels among Sri Lankan women with well-characterized PCOS. Consecutive women with PCOS manifesting from adolescence (n=55) and adult controls (n=110) were recruited. Serum kisspeptin and testosterone levels were determined by ELISA method. Whole gene sequencing was performed to identify the polymorphisms in Kiss1 and GPR54 genes. Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS than controls: kisspeptin 4.873nmol/L versus 4.127nmol/L; testosterone 4.713nmol/L versus 3.415 nmol/L, p<0.05. Sequencing the GPR54 gene revealed 5 single nucleotide polymorphisms (SNPs), rs10407968, rs1250729403, rs350131, chr19:918686, and chr19:918735, with two novel SNPs (chr19:918686 and chr19:918735), while sequencing the Kiss1 gene revealed 2 SNPs, rs5780218 and rs4889. All identified SNPs showed no significant difference in frequency between patients and controls. GPR54 gene rs350131 polymorphism (G/T) was detected more frequently in our study population. The heterozygous allele (AG) of GPR54 gene novel polymorphism chr19:918686 showed a marginal association with serum kisspeptin levels (p=0.053). Genetic variations in GPR54 and Kiss1 genes are unlikely to be associated with PCOS among Sri Lankan women manifesting from adolescence. Meanwhile the heterozygous allele of chr19:918686 is probably associated with serum kisspeptin concentrations, which suggests a potential role in the aetiology of PCOS.
PPAR-γ Activation Exerts an Anti-inflammatory Effect by Suppressing the NLRP3 Inflammasome in Spinal Cord-Derived Neurons
Authors: Meng Qing-Qi , Feng Zhen-Cheng , Zhang Xing-Liang , Hu Li-Qiong , Wang Min , Zhang Hai-Feng , Li Si-Ming
Published: March 2019

Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR-γ activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF-κB in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR-γ agonist) inhibited the expression of caspase-1. In in vitro neurons, G3335 (PPAR-γ antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1β), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1β, and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR-γ activation. NF-κB did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our in vitro results, we verified that locomotor recovery of SCI rats in vivo was regulated via PPAR-γ, NLRP3, and NF-κB. These results suggest that PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome—but not NF-κB—in neurons and that PPAR-γ activation is a promising therapeutic target for SCI.
Adaptability of Turbulence Models for Pantograph Aerodynamic Noise Simulation
Authors: Tan Xiao-ming , Xie Peng-peng , Yang Zhi-gang , Gao Jian-yong
Published: March 2019

This study was targeted at CX‐PG‐type Faiveley pantograph of high‐speed train and cylinders and analysed the fluctuating flow field around these objects by using the large eddy simulation (LES) model, the scale adaptive simulation (SAS) model, the improved delayed detached eddy simulation with shear‐stress transport‐kω (IDDES sst‐kω) model, the delayed detached eddy simulation with shear‐stress transport‐kω (DDES sst‐kω) model, and the delayed detached eddy simulation with realizable‐kε (DDES R‐kε) model. The space distributions of velocity, vorticity, and vortex structures were compared to investigate their performances on simulating fluctuating flow fields and computing aeroacoustic sources through Fourier transformation based on the surface fluctuating pressures. Furthermore, the far‐field radiated noise was calculated based on the Ffowcs Williams–Hawkings equation. Based on the computation precision of the five models, a feasible turbulent model was selected for simulating aerodynamic noise. The relative errors to the results from wind‐tunnel experiments of the sound pressure level (SPL) were obtained as 0.7%, 1.6%, 7.8%, 3.8%, and 12.1%, respectively, and the peak Strouhal numbers were obtained as 2.0%, 8.5%, 5.5%, 11.5%, and 51.0% for cylinder simulation. Moreover, the relative errors of SAS, IDDES sst‐kω, DDES sst‐kω, and DDES R‐kε models to the result from LES of SPL were respectively obtained as 2.3%, 4.5%, 5.6%, and 10.8% for pantograph. Thus, it is conclusive that none of the aforementioned models are comparable with the LES model with respect to the precision in the aeroacoustic simulation. However, SAS, IDDES sst‐kω, and DDES sst‐kω are practically competent with the LES model considering the numerical simulations with respect to the engineering computation precision. The numerical computation model was verified using the wind‐tunnel test results.
Influence of Land-Use Type on Forest Bird Community Composition in Mount Kenya Forest
Authors: Mahiga Samuel N. , Webala Paul , Mware Mugo J. , Ndang’ang’a Paul K.
Published: March 2019

Few studies have explored how human land uses influence and support persistence of forest biodiversity in central Kenya. In the case of the Mount Kenya ecosystem, farmlands and plantation forests are significant land-use types. Using point counts, we assessed bird communities in natural forests, plantation forests, and farmlands in the Nanyuki Forest Block, Western Mount Kenya. Bird point counts were undertaken during two sampling periods (wet and dry season). Compared to farmlands and plantation forest, natural forest had the highest overall avian species richness and relative species richness of all except one forest-dependent foraging guild (granivores) and nonforest species, which occurred frequently only on farmlands. Plantation forest had the lowest relative richness of all avian habitat and foraging guilds. Conversely, specialist forest-dependent species mainly occurred in the structurally complex remnant natural forest. Our study underscores the importance of remnant natural forests for the persistence and conservation of forest biodiversity and risks posed by replacing them with plantation forests and farmlands.
Phytoplankton and Its Role in Accumulation of Microelements in Bottom Deposits of Azov Sea
Authors: Dotsenko Irina V. , Mikhailenko Anna V.
Published: March 2019

The importance of phytoplankton is high in transformation of substances in aquatic ecosystems and in formation of suspension’s material structure. Its main functions are consumption of the dissolved biogenic components and chemical elements and their conversion to a firm phase. The article is devoted to the bioaccumulation of microelements by phytoplankton in the ecosystem of the Azov Sea. The fact that the algal biomass during the periods of blooming in the sea reaches 1,400 g/l makes this study especially urgent. The authors define the rates of biogeochemical cycle and the intensity of chemical elements’ consumption and also investigate the role of phytoplankton in the formation chemical peculiarities of bottom deposits and its involvement in sedimentogenesis in the Azov Sea. The cause of the reduced trace element content in bottom deposits relatively to suspended material is established. It is noted that the amount of some elements annually consumed by algae of the Azov Sea is up to 75% from their maximum delivery by terrigenous material.
Effect of Isothermal Treatment on Microstructure and Mechanical Properties of Cold-Deformed IF Steel
Authors: Reyes Barragan Jose Luis , Rodriguez Diaz Roberto Ademar , Ojeda Martinez Maria Luisa , Gaona Jimenez Silvia , Juarez Islas Julio Alberto
Published: March 2019

In this study, we investigated the recrystallisation kinetics of Ti-stabilised interstitial-free (IF) steel manufactured by the Mexican steel industry through the route of electric arc furnace with vacuum degassing, secondary refining, and subsequent continuous casting. The IF steel was hot-rolled at 950°C and then cold-rolled until deformation of 94% was attained, followed by recrystallisation at different times at a constant temperature of 780°C. In addition, the mechanical properties of the IF steel were assessed as a function of recrystallisation time. The results obtained from the mechanical property tests were presented in the form of plots of microhardness, yield strength, ultimate tensile stress, and deformation percent as functions of the recrystallised fraction with an indirect dependence on recrystallisation time. A graphical model of the recrystallisation behaviour showed the evolution of the microstructure, including phase transformations, hardness, and the mechanical properties determined from the tensile tests. In view of subsequent recovery and recrystallisation, stored energy analysis derived from the strain induced by deformation was presented. Furthermore, we determined the precipitates formed in the different processing stages of IF steel.
Design of Additively Manufactured Structures for Biomedical Applications: A Review of the Additive Manufacturing Processes Applied to the Biomedical Sector
Authors: Calignano Flaviana , Galati Manuela , Iuliano Luca , Minetola Paolo
Published: March 2019

Additive manufacturing (AM) is a disruptive technology as it pushes the frontier of manufacturing towards a new design perspective, such as the ability to shape geometries that cannot be formed with any other traditional technique. AM has today shown successful applications in several fields such as the biomedical sector in which it provides a relatively fast and effective way to solve even complex medical cases. From this point of view, the purpose of this paper is to illustrate AM technologies currently used in the medical field and their benefits along with contemporary. The review highlights differences in processes, materials, and design of additive manufacturing techniques used in biomedical applications. Successful case studies are presented to emphasise the potentiality of AM processes. The presented review supports improvements in materials and design for future researches in biomedical surgeries using instruments and implants made by AM.
Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis
Authors: Natarajan Suchitra , Foreman Kaitlyn M. , Soriano Michaela I. , Rossen Ninna S. , Shehade Hussein , Fregoso Daniel R. , Eggold Joshua T. , Krishnan Venkatesh , Dorigo Oliver , Krieg Adam J. , Heilshorn Sarah C. , Sinha Subarna , Fuh Katherine C. , Rankin Erinn B.
Published: March 2019

Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here, we report that the HGSOC tumor-mesothelial niche was hypoxic, and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC.

Significance:

This study identifies HIF/LOX signaling as a potential therapeutic target to inhibit collagen remodeling and tumor progression in HGSOC.
Randomly Distributed K14+ Breast Tumor Cells Polarize to the Leading Edge and Guide Collective Migration in Response to Chemical and Mechanical Environmental Cues
Authors: Hwang Priscilla Y. , Brenot Audrey , King Ashley C. , Longmore Gregory D. , George Steven C.
Published: March 2019

Collective cell migration is an adaptive, coordinated interactive process involving cell–cell and cell–extracellular matrix (ECM) microenvironmental interactions. A critical aspect of collective migration is the sensing and establishment of directional movement. It has been proposed that a subgroup of cells known as leader cells localize at the front edge of a collectively migrating cluster and are responsible for directing migration. However, it is unknown how and when leader cells arrive at the front edge and what environmental cues dictate leader cell development and behavior. Here, we addressed these questions by combining a microfluidic device design that mimics multiple tumor microenvironmental cues concurrently with biologically relevant primary, heterogeneous tumor cell organoids. Prior to migration, breast tumor leader cells (K14+) were present throughout a tumor organoid and migrated (polarized) to the leading edge in response to biochemical and biomechanical cues. Impairment of either CXCR4 (biochemical responsive) or the collagen receptor DDR2 (biomechanical responsive) abrogated polarization of leader cells and directed collective migration. This work demonstrates that K14+ leader cells utilize both chemical and mechanical cues from the microenvironment to polarize to the leading edge of collectively migrating tumors.

Significance:

These findings demonstrate that pre-existing, randomly distributed leader cells within primary tumor organoids use CXCR4 and DDR2 to polarize to the leading edge and direct migration.
Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling
Authors: Madak-Erdogan Zeynep , Band Shoham , Zhao Yiru C. , Smith Brandi P. , Kulkoyluoglu-Cotul Eylem , Zuo Qianying , Santaliz Casiano Ashlie , Wrobel Kinga , Rossi Gianluigi , Smith Rebecca L. , Kim Sung Hoon , Katzenellenbogen John A. , Johnson Mariah L. , Patel Meera , Marino Natascia , Storniolo Anna Maria V. , Flaws Jodi A.
Published: March 2019

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER+) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER+ breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER+ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER+ breast cancers in obese postmenopausal women.

Significance:

These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.
Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM+ Hepatocellular Carcinoma
Authors: Takai Atsushi , Dang Hien , Oishi Naoki , Khatib Subreen , Martin Sean P. , Dominguez Dana A. , Luo Ji , Bagni Rachel , Wu Xiaolin , Powell Katie , Ye Qing-Hai , Jia Hu-Liang , Qin Lun-Xiu , Chen Jinqiu , Mitchell Gary A. , Luo Xiaoling , Thorgeirsson Snorri S. , Wang Xin Wei
Published: March 2019

Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell–like EpCAM+AFP+ HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM+AFP+ HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM+ HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM+ HCC subpopulations.

Significance:

This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM+ HCC tumors by inactivating the Wnt/β-catenin signaling pathway.
Distinctive and Pervasive Alterations of Functional Brain Networks in Cerebral Small Vessel Disease with and without Cognitive Impairment
Authors: Liu Renyuan , Wu Wenhui , Ye Qing , Gu Yucheng , Zou Junhui , Chen Xin , Jiang Yongcheng , Bai Feng , Xu Yun , Wang Chun
Published: March 2019

Objective: To explore the within- and between-network patterns of the default mode network (DMN), the frontoparietal control network (FPCN), and the dorsal attention network (DAN) in cerebral small vessel disease (CSVD) with and without cognitive impairment (CI). Methods: Twenty CSVD with CI subjects, 21 CSVD without CI subjects, and 25 healthy elderly controls were recruited. The within- and between-network patterns of the networks were identified based on resting-state functional magnetic resonance imaging data. Results: Compared with the control group, both the CSVD with CI group and the CSVD without CI group displayed decreased within-network function of the DMN and lower negative connectivity between the DMN and other networks (i.e., DMN and DAN, DMN and FPCN), whereas the CSVD with CI group additionally showed within- and between-network alterations of the FPCN (i.e., increased within-network function of the FPCN and lower negative connectivity between the FPCN and the DMN). Furthermore, these alterations of the FPCN were correlated with the cognitive function of CSVD subjects. Interestingly, the between-network connectivity of the FPCN and the DMN was negatively correlated with deep white matter hyperintensities (DWMH) volume in CSVD subjects. Conclusion: These findings suggest that cognitive alterations of CSVD subjects may be mainly regulated by the FPCN that correlates with DWMH burden, and shed light on the investigation of surrogate markers of CSVD.
Language in Amnestic Mild Cognitive Impairment and Dementia of Alzheimer’s Type: Quantitatively or Qualitatively Different?
Authors: Jokel Regina , Seixas Lima Bruna , Fernandez Alita , Murphy Kelly J.
Published: March 2019

Background/Aims: The purpose of this study was to explore language differences between individuals diagnosed with amnestic mild cognitive impairment multiple domain (aMCIm) and those with probable Alzheimer’s disease, with a goal of (i) characterizing the language profile of aMCIm and (ii) determining whether the profiles of dementia of Alzheimer’s type (DAT) and aMCIm individuals are on a continuum of one diagnostic entity or represent two distinct ­cognitive disorders. Methods: Language data from 28 patients with consensus diagnosis of aMCIm and DAT derived from a retrospective chart review were compared to that of healthy controls. Results: A non-parametric statistic established that there was no significant difference between groups in age, years of education or duration of symptoms and that expressive language was found to be relatively intact in both patient groups. In contrast, both groups exhibited significant impairments on receptive language tests and on linguistically complex tasks that rely on episodic memory and executive functions. Individuals with aMCIm and DAT present with configurations of language features that are largely in parallel to each other and reflect predominantly quantitative differences. Conclusion: Language tests provide an important contribution to the diagnostic process in their capacity to identify language impairments at an early stage. Understanding the nature of language decline is critically important to the intervention process as this information would inform cognitive intervention approaches aimed at promoting quality of life in people living with MCI and dementia.
Prevalence of C9ORF72 Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus
Authors: Korhonen Ville E. , Remes Anne M. , Helisalmi Seppo , Rauramaa Tuomas , Sutela Anna , Vanninen Ritva , Suhonen Noora-Maria , Haapasalo Annakaisa , Hiltunen Mikko , Jääskeläinen Juha E. , Soininen Hilkka , Koivisto Anne M. , Leinonen Ville
Published: March 2019

Background/Aims: The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH). Methods: We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age > 65 years). Results: While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52–67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. Conclusion: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.
Resíduo de mármore como atenuador de efluente ácido
Authors: Neves Mirna Aparecida , Taguchi Simone Pereira , Silva Douglas Rosa da , Vieira Fabrício Thiengo
Published: March 2019

Dimension stones are worldwide used as building and finishing material, reason why the environmental problems inherent to this productive sector became relevant in various countries. One of these problems is the production of large amounts of wastes during the sawing of rocky blocks and polishing of plates. The waste generated by cutting marble with diamond wire consists of fine particles of calcium and magnesium carbonate dispersed in water. This mud has basic character, and it is destined to drying beds or open pit deposits. In parallel, many production processes generate hazardous acidic effluents, which disposal is a serious and global problem. The pH of these solutions must be neutralized or, at least, raised to levels that are considered safe by environmental regulations. In this work, a strong acid solution was treated with varying amounts of marble waste coming from the dimension stone industry. The treatment generated secondary solid and liquid phases that were analyzed to determine the feasibility of their disposal in landfills. The waste raised the pH of the acid solution from near 1.0 to values between 5.0 and 6.0, which are acceptable levels for non-dangerous effluents. Besides that, loss of up to 50% in mass occurred, diminishing the amount of the primary solid waste. By the other hand, the levels of total dissolved solids (TDS), Cu, chlorides and nitrates on the liquid phase of the effluent remained higher than that allowed by environmental legislation for discharge into water bodies. Nevertheless, their characteristics correspond to non-hazardous and non-inert wastes, which, after dried, can be discarded in ordinary waste landfills.
Francisco António de Sampaio e sua História Natural da Vila da Cachoeira: Circulação, reconfiguração e validação da produção de conhecimento na segunda metade do século XVIII
Authors: Conceição Gisele Cristina da
Published: March 2019

O objetivo deste artigo é compreender os processos de construção de conhecimento sobre a natureza do Brasil, no século XVIII, a partir do estudo de caso de Francisco António de Sampaio e seu trabalho de filosofia natural. Busco compreender tais processos como sendo resultantes de dinâmicas de circulação de conhecimento, trocas e negociações, e o estabelecimento de relações de poder entre os agentes envolvidos neste processo. Pretendo demonstrar como estas dimensões foram fundamentais para o processo de produção de trabalhos científicos nos espaços coloniais, bem como para sua circulação e a validação pelos círculos letrados metropolitanos.
Relegado à invisibilidade. O lugar dos direitos humanos na agenda da diplomacia franquista (1945-1955)
Authors: Ribeiro Mariana Cardoso dos Santos
Published: March 2019

Entre 1945 e 1955, a tática oficial do governo franquista foi contestar publicamente as acusações dirigidas contra o regime, considerado no pós-guerra como uma persistência do fascismo derrotado. Neste artigo, sustentamos que, frente à ONU, a ação exterior foi além da negativa de fatos – ocorrências de violações de direitos na Espanha –, mas dirigiu-se a relegá-los à invisibilidade e, assim, produzir o esquecimento a respeito do assunto. A partir da avaliação crítica de correspondência diplomática e de documentos oficiais da Nações Unidas revelamos que a diplomacia franquista utilizou duas vias de ação principais: não responder quando instada a explicar-se sobre práticas de violação de direitos humanos em território espanhol; e obter de seus aliados mais próximos o silêncio sobre o assunto nos foros internacionais.
Um intelectual na mira da repressão: Milton Santos e o golpe de 1964
Authors: Lima Thiago Machado de
Published: March 2019

Este artigo analisa a experiência de repressão política sofrida por Milton Santos em consequência da instauração do golpe civil-militar de 31 de março de 1964 que destituiu o governo do presidente João Goulart. A problemática central se concentra  na compreensão do processo de prisão e exílio do geógrafo e o que esses fatos representaram na sua trajetória. O texto tem como base documental fontes jornalísticas, militares e entrevistas e toma como referencial teórico as concepções de Jean François Sirinelli e Michel Pollack. Espera-se contribuir para elucidar aspectos ainda pouco investigados da trajetória política e intelectual de Milton Santos, enfatizando que o golpe de 1964 representou uma inflexão na vida de intelectuais brasileiros que estiveram sintonizados com ideais progressistas e empreenderam lutas na defesa de uma sociedade mais igualitária.
Questão Christie em perspectiva global: Pressão britânica, Guerra Civil norte-americana e o início da crise da escravidão brasileira (1860-1864)
Authors: Youssef Alain El
Published: March 2019

Os trabalhos que analisaram a Questão Christie valeram-se da premissa de que os eventos que resultaram no rompimento diplomático entre Brasil e Inglaterra (1863-1865) podem ser explicados exclusivamente pela relação bilateral entre os dois países. Sem negar por completo essa dimensão, o artigo tem por objetivo ampliar a unidade de análise do tema, de modo a verificar como outros processos históricos em curso na década de 1860 tiveram papel decisivo no entrevero entre os dois países. Com base em artigos de jornal, anais parlamentares e correspondências diplomáticas, o texto pretende demonstrar que a Questão Christie também esteve relacionada à conjuntura histórica aberta pela Guerra Civil norte-americana e, assim, verificar suas consequências mais imediatas para a instauração da crise da escravidão brasileira.
A prisão de Pedro Ivo e o debate político após a Praieira, 1849-1854
Authors: Oliveira Maria Luiza Ferreira
Published: March 2019

Nesse artigo reconstituímos a ampla e quase desconhecida polêmica em torno da prisão de Pedro Ivo em maio de 1850 no Rio de Janeiro. Depois procuramos esclarecer o teor do debate político do tempo, ressaltando a força da bandeira por uma Assembleia Constituinte, encampada por mais de uma dezena de periódicos liberais. Seguimos acompanhando o impacto da fuga de Pedro Ivo, o grandioso banquete da “regeneração nacional” e a repentina morte, eventos que marcaram o imaginário da época. Os eventos repercutiram inclusive entre os povos das matas de Alagoas, por isso abordamos a reação do diretor da Colônia Militar e o esforço de “desinfestação” do território. Estava em pauta uma disputa de narrativas, tanto da atuação de Pedro Ivo, bandido ou herói, como da própria memória da Rebelião Praieira. Ao mesmo tempo, havia naqueles anos diferentes projetos de futuro para o país.
Insights into the feeding ecology of and threats to Sand Cat Felis margarita Loche, 1858 (Mammalia: Carnivora: Felidae) in the Kyzylkum Desert, Uzbekistan
Authors: Brighten Alex Leigh , Burnside Robert John
Published: March 2019

Little is known about the ecology of the Sand Cat Felis margarita throughout its range in the deserts of northern Africa to central Asia.  We present observations of the Sand Cat in the southern Kyzylkum Desert, Uzbekistan, potentially preying upon a large bird and returning to the kill on subsequent nights.  This record contributes to the knowledge about the feeding ecology and varied diet of the Sand Cat and its opportunistic hunting strategy.
Abstract 006: Role of Endothelial YingYang1 in Controlling Angiogenetic Sprouting and Maturation
Authors: Zhang Shuya , Kim Ji Young , Suowen Xu Suowen , Koroleva Marina , Jin Zhenggen
Published: March 2019

Angiogenesis is essential for growth and repair, and irregularity of angiogenesis contributes to numerous malignant, inflammatory and ischemic disorders. Transcription factors that regulate angiogenic gene expression are critical for proper vascular development and homeostasis. Here we show that YingYang1( YY1) is essential for vascular development both in embryonic and postnatal angiogenesis. We first found that endothelium-specific deletion of YY1 leads to embryonic lethality due to vascular defects. We further found inducible endothelial YY1 knockout (YY1
iΔEC
) mice exhibited abnormality of sprouting angiogenesis with a blunted-end, aneurysm-like structure with fewer and dysmorphic filopodia in EC tip cells compared with those of wild-type mice. Similar results are also identified in vitro by using cultured HUVEC cells. Moreover, we found that endothelial deletion of YY1 also leads to severe impairments in retinal vessel remodeling and maturation. Mechanistically, we show that YY1 is a robust endogenous inhibitor of Notch1 signaling that controls explicitly endothelial cell fate. YY1 deficiency remarkably enhances Hey1 expression, resulting in impaired retinal sprouting angiogenesis, which can be rescued by the treatment of the Notch inhibitor. Furthermore, YY1 regulates Hey1 expression by binding to RBP-J via a highly conserved ankyrin (ANK) repeat domain, then inhibits the NICD-MAML1- RBPJ complex formation by competing with MAML1 binding to RBP-J, which attenuates expression of downstream target genes Hey1. Lastly, we found that tumor growth and angiogenesis is reduced significantly in YY1
iΔEC
mice, suggesting that endothelial YY1 is required for pathological angiogenesis in mouse tumor models. Altogether, our study reveals a new role for YY1 as a central mediator of Notch signaling and an essential regulator in both physiologic and pathologic angiogenesis.
Abstract 007: Athero-protective Flow Regulation of ITPR3: an Epigenetic Approach
Authors: He Ming , Huang Tse-Shun , Martin Marcy , Chien Shu , Shyy John
Published: March 2019

Background:
The topographic distribution of atherosclerosis in human vasculature underscores the role of shear stress in regulating gene expression and function in the endothelium. Recent advances in understanding of mechanotransduction reveal that epigenetic regulation is integral to shear stress-mediated gene expression. With the use of ChIP-seq and ATAC-seq, the current study aims to demonstrate the link between histone modifications and transcriptional regulation in endothelial cells (ECs) in response to shear stress.

Methods and Results:
We found that pulsatile shear (PS)- and oscillatory shear (OS)-induced differential H3K27ac enrichments were associated with adjacent gene expression in ECs, approximately 30% of which showed significant positive correlation (Pearson’s correlation coefficient >0.7).
In silico
prediction revealed that Krüppel-like factor 4 (KLF4) binding motifs were enriched in the PS-enhanced H3K27ac regions. By integrating genes that are induced by PS, have the KLF4 binding loci, and contain PS-associated H3K27ac in their promoter regions, we identified 18 novel PS-upregulated genes. Validating these results in mouse ECs isolated from intima of the thoracic aorta vs aortic arch, lung ECs from EC-KLF4-TG vs EC-KLF4-KO mice, and atorvastatin-treated vs control ECs, we found that Inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) had the most robust expression in multiple systems. Consistent with these findings, ATAC-seq and ChIP-qPCR demonstrated a specific locus in the promoter region of the ITPR3 gene that was essential for KLF4 binding, H3K27ac enrichment, chromatin accessibility, and ITPR3 transcription. Deletion of this KLF4 binding locus in ECs by using CRISPR-Cas9 resulted in blunted calcium influx, reduced eNOS expression, and diminished NO bioavailability. Furthermore, ITPR-KO mice fed an atherogenic diet resulted in exacerbated atherosclerosis compared to wildtype littermates.

Conclusions:
Using a multi-layer systems approach, we have demonstrated that KLF4 is crucial for the histone modifications that allow the transcriptional activation of ITPR3 in ECs. This novel mechanism contributes to Ca2
+
-dependent eNOS activation and EC homeostasis by maintaining an athero-protective phenotype.
Abstract 011: Cardiovascular Consequences of Cantu Syndrome and Response to Glibenclamide Treatment in Two Novel KATP Channel Mutant Mouse Models
Authors: McClenaghan Conor , Huang Yan , Harter Theresa , Brown G. Schuyler , Hinman Kristina , Halabi Carmen , Matkovich Scot , Mecham Robert P , Weinheimer Carla J , Kovacs Attila , England Sarah , Remedi Maria S , Nichols Colin G
Published: March 2019

The rare heritable disorder Cantů syndrome (CS) arises from gain-of-function mutations in the genes encoding the cardiovascular KATP channel subunits Kir6.1 and SUR2 (
KCNJ8
and
ABCC9
, respectively). CS is characterized by diverse features including hypertrichosis, osteochondrodysplasia and craniofacial dysmorphology. Multiple cardiovascular abnormalities are also reported in CS including vascular dilation and tortuosity, dramatic cardiomegaly, pulmonary hypertension and low systemic blood pressure. We have developed and characterized two novel mouse models of Cantu Syndrome in which disease causing amino acid substitutions have been engineered into either Kir6.1 (p.V65M) or SUR2 (p.A478V) using CRISPR/Cas9 genome editing. Electrophysiological assessment of isolated vascular smooth muscle cells (VSMCs) showed that both mutations result in increased basal activity of VSM KATP channels. Mutant mice also exhibit vascular dilation, low blood pressure, and pulmonary hypertension. In addition, mutant mice exhibited hypertrophic, hyper-contractile hearts. The latter findings are not trivially predictable as a consequence of KATP gain-of-function, but also recapitulates key clinical features of CS. The severity of pathophysiological remodeling correlated with the molecular effects of the substitution. These models provide novel insights to the cardiovascular consequences of KATP over-activity. Little is known about the long-term effects of human CS, nor reversibility of pathophysiological consequences. Chronic administration of the sulfonylurea KATP inhibitor glibenclamide (glyburide) by slow-release pellets implanted under the skin resulted in normalization of vascular consequences and reversal of cardiac hypertrophy in SUR2(A478V) mice over 3 weeks. Kir6.1(V65M) mice are less sensitive to glibenclamide treatment, as predicted from studies of recombinant channels. These results suggest that glibenclamide represents a promising pharmacotherapy for CS (but that sensitivity may be patient- and mutation-dependent), and perhaps for diverse cardiovascular conditions arising from decreased smooth muscle excitability in general.