bluuebunny/crossref_metadata_2025 huggingface dataset:
Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis
Authors: Gautam Jaya , Banskota Suhrid , Lee Hyunji , Lee Yu-Jeong , Jeon Yong Hyun , Kim Jung-Ae , Jeong Byeong-Seon
Published: September 2018

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer with poor prognosis. In the present study, we demonstrated that Src, a non-receptor tyrosine kinase, might provide an effective therapeutic strategy to overcome TNBC invasion and metastasis, which are mediated via the synergistic action of the lysosomal enzyme cathepsin S (CTSS) and gelatinase MMP-9. Knock-down of MMP-9 and CTSS using siRNAs resulted in a synergistic suppression of MDA-MB-231 cell invasion, which was similarly observed with pharmacological inhibitors. During the screening of new drug candidates that suppress both CTSS and MMP-9, BJ-2302, a novel 7-azaindolin-2-one derivative, was discovered. Src, an upstream activator of both pathways (PI3K/Akt and Ras/Raf/ERK) responsible for the expression of CTSS and MMP-9, was identified as a high-affinity target of BJ-2302 (IC90: 3.23 µM) through a Src kinase assay and a drug affinity responsive target stability (DARTS) assay. BJ-2302 effectively suppressed MDA-MB-231 cell invasion (Matrigel invasion assay) and metastasis (chorioallantoic membrane assay xenografted with MDA-MB-231-luc2-tdTomato cancer cells). Unlike Z-FL-COCHO (potent CTSS inhibitor), BJ-2302 did not induce any cytotoxicity in MCF-10A normal breast epithelial cells. Additionally, BJ-2302 (1 mg/kg) strongly suppressed TNBC cell proliferation in vitro and tumor growth in a xenograft mouse tumor model. The anti-metastatic and anti-tumor effects of BJ-2302 were superior to those of Z-FL-COCHO (1 mg/kg) or batimastat (30 mg/kg), a pan-MMP inhibitor. In summary, inhibition of Src kinase suppressed TNBC tumor growth and metastasis, and Src inhibitors such as BJ-2302 may constitute a novel therapeutic tool to treat breast cancer that expresses high levels of CTSS and MMP-9.
On-chip excitation of single germanium vacancies in nanodiamonds embedded in plasmonic waveguides
Authors: Siampour Hamidreza , Kumar Shailesh , Davydov Valery A. , Kulikova Liudmila F. , Agafonov Viatcheslav N. , Bozhevolnyi Sergey I.
Published: September 2018

Monolithic integration of quantum emitters in nanoscale plasmonic circuitry requires low-loss plasmonic configurations capable of confining light well below the diffraction limit. We demonstrated on-chip remote excitation of nanodiamond-embedded single quantum emitters by plasmonic modes of dielectric ridges atop colloidal silver crystals. The nanodiamonds were produced to incorporate single germanium-vacancy (GeV) centres, providing bright, spectrally narrow and stable single-photon sources suitable for highly integrated circuits. Using electron-beam lithography with hydrogen silsesquioxane (HSQ) resist, dielectric-loaded surface plasmon polariton waveguides (DLSPPWs) were fabricated on single crystalline silver plates to contain those of deposited nanodiamonds that are found to feature appropriate single GeV centres. The low-loss plasmonic configuration enabled the 532-nm pump laser light to propagate on-chip in the DLSPPW and reach to an embedded nanodiamond where a single GeV centre was incorporated. The remote GeV emitter was thereby excited and coupled to spatially confined DLSPPW modes with an outstanding figure-of-merit of 180 due to a ~six-fold Purcell enhancement, ~56% coupling efficiency and ~33 μm transmission length, thereby opening new avenues for the implementation of nanoscale functional quantum devices.
Diabetes knowledge and its association with the weight status among residents of Jeddah City, Saudi Arabia
Authors: Kutbi Hebah A. , Mosli Hala H. , Alhasan Ahmed H. , Mosli Rana H.
Published: September 2018

Objective

To examine the association of weight status with level of diabetes knowledge (symptoms and complications) among residents of Jeddah City, Saudi Arabia.

Methods

In a cross-sectional study, a questionnaire assessing sociodemographic and health characteristics and knowledge about diabetes and its symptoms and complications was utilized. Data of 3978 adults, 18 years of age or older, were collected from public mall sites in Jeddah city and surrounding areas. Participants were divided into three tertiles based on their knowledge scores. Weight and height were measured following standardized procedures, and body weight categories were defined based on body mass index (BMI). The association between weight status and tertiles of diabetes knowledge was examined using multinomial logistic regression analysis.

Results

Compared to normal-weight participants, participants who were underweight, overweight, or obese, did not differ with regards to knowledge about diabetes symptoms. Adjusted models showed that overweight and obese participants had lower odds of being in the lowest tertile of knowledge about diabetes complications compared to normal-weight participants (OR: 0.71, 95% CI: 0.58–0.86 and OR: 0.64, 95% CI: 0.51–0.79, respectively). With regards to general knowledge about diabetes, the knowledge of participants who were underweight did not differ when compared to normal-weight participants. Overweight and obese participants had lower odds of being in the lowest tertile of general knowledge about diabetes compared to normal-weight participants (OR: 0.78, 95% CI: 0.62–0.97 and OR: 0.60, 95% CI: 0.47–0.76, respectively).

Conclusions

Overweight and obese individuals have better knowledge about diabetes compared to normal-weight individuals. Public health programs need to take into account the level of diabetes knowledge and tailor interventions to aid behavior and lifestyle change.
Alcohol-induced autophagy via upregulation of PIASy promotes HCV replication in human hepatoma cells
Authors: Ran Meihua , Chen Hui , Liang Bingyu , Liao Weibo , Jiang Junjun , Huang Jiegang , Ning Chuanyi , Zang Ning , Zhou Bo , Liao Yanyan , Liu Huifang , Qin Fengxiang , Yang Quanlue , Li Jieliang , Ho Wenzhe , Liang Hao , Ye Li
Published: September 2018

Both alcohol and hepatitis C virus (HCV) infection could induce cellular autophagy in liver cells, which is considered to be essential for productive HCV replication. However, whether alcohol-induced autophagy is involved in the pathogenesis of HCV infection is still poorly understood. Alcohol treatment could induce autophagy in Huh7 cells (a hepatoma cell line that supports HCV JFH-1 replication), evidenced by the increase of LC3B-II levels, the conversion of LC3B-I to LC3B-II, and the formation of GFP-LC3 puncta as well as the decrease of p62 level in alcohol-treated cells compared with control cells. Alcohol treatment also significantly increased PIASy (a member of the PIAS family) expression, which can act as a SUMO (small ubiquitin-like modifier protein) E3 ligase to regulate a broader range of cellular processes including autophagy. Overexpression or the silencing expression of PIASy in alcohol-treated Huh7 cells could increase or decrease autophagic activation caused by alcohol treatment, respectively, and thus affect HCV replication correspondingly. In the absence of alcohol, overexpression or silencing expression of PIASy increase or decrease the level of cellular autophagy, judged by the changes of LC3B-II and p62 levels in the presence or absence of chloroquine (CQ), a lysosome inhibitor. More importantly, in the presence of 3-methyladenine (3-MA), an inhibitor in the early stage of autophagy, the effects of overexpression or silencing expression of PIASy on HCV replication were largely blocked. Furthermore, PIASy could selectively drive the accumulation of SUMO1-conjugated proteins, along with upregulation of the expression of several important autophagy factors, including ATG7 and ATG5–ATG12. In conclusion, alcohol promotes HCV replication through activation of autophagy in Huh7 cells, which partly attributes to its induction of PIASy expression. PIASy-enhanced accumulation of SUMO1-conjugated proteins may contribute to its inducing effect of autophagy. Our findings provide a novel mechanism for the action of alcohol-promoting HCV replication in the context of cellular autophagy.
Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1α signaling pathway in liver inflammatory injury
Authors: Zhu Qiang , Wang Han , Jiang Bin , Ni Xuhao , Jiang Longfeng , Li Changyong , Wang Xuehao , Zhang Feng , Ke Bibo , Lu Ling
Published: September 2018

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays important roles in regulating immune and metabolic homeostasis. Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) transcription factors are crucial for the regulation of immune cell function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1α activity, leading to Foxp3 downregulation and RORγt and IL-17A upregulation in IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1α and upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. Silencing of HIF-1α in ATF3 KO mice ameliorated IRI-induced liver damage in parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1α signaling, which was crucial for the modulation of TLR4-driven inflammatory responses and T cell development. The present study provides potential therapeutic targets for the treatment of liver IRI followed by liver transplantation.
TNFα sensitizes hepatocytes to FasL-induced apoptosis by NFκB-mediated Fas upregulation
Authors: Faletti Laura , Peintner Lukas , Neumann Simon , Sandler Sandra , Grabinger Thomas , Mac Nelly Sabine , Merfort Irmgard , Huang Chun-Hao , Tschaharganeh Darjus , Kang Tae-Won , Heinzmann Florian , D’Artista Luana , Maurer Ulrich , Brunner Thomas , Lowe Scott , Zender Lars , Borner Christoph
Published: September 2018

Although it is well established that TNFα contributes to hepatitis, liver failure and associated hepatocarcinogenesis via the regulation of inflammation, its pro-apoptotic role in the liver has remained enigmatic. On its own, TNFα is unable to trigger apoptosis. However, when combined with the transcriptional inhibitor GaLN, it can cause hepatocyte apoptosis and liver failure in mice. Moreover, along with others, we have shown that TNFα is capable of sensitizing cells to FasL- or drug-induced cell death via c-Jun N-terminal kinase (JNK) activation and phosphorylation/activation of the BH3-only protein Bim. In this context, TNFα could exacerbate hepatocyte cell death during simultaneous inflammatory and T-cell-mediated immune responses in the liver. Here we show that TNFα sensitizes primary hepatocytes, established hepatocyte cell lines and mouse embryo fibroblasts to FasL-induced apoptosis by the transcriptional induction and higher surface expression of Fas via the NFκB pathway. Genetic deletion, diminished expression or dominant-negative inhibition of the NFκB subunit p65 resulted in lower Fas expression and inhibited TNFα-induced Fas upregulation and sensitization to FasL-induced cell death. By hydrodynamic injection of p65 shRNA into the tail vein of mice, we confirm that Fas upregulation by TNFα is also NFκB-mediated in the liver. In conclusion, TNFα sensitization of FasL-induced apoptosis in the liver proceeds via two parallel signaling pathways, activation of JNK and Bim phosphorylation and NFκB-mediated Fas upregulation.
Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations
Authors: Chang Jiang , Tian Jianbo , Zhu Ying , Zhong Rong , Zhai Kan , Li Jiaoyuan , Ke Juntao , Han QiangQiang , Lou Jiao , Chen Wei , Zhu Beibei , Shen Na , Zhang Yi , Gong Yajie , Yang Yang , Zou Danyi , Peng Xiating , Zhang Zhi , Zhang Xuemei , Huang Kun , Yang Ming , Wang Li , Wu Chen , Lin Dongxin , Miao Xiaoping
Published: September 2018

Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48–2.12, P = 5.35 × 10−10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50–2.27, P = 4.34 × 10−9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72–3.16, P = 4.21 × 10−8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.
User considerations in assessing pharmacogenomic tests and their clinical support tools
Authors: Mukerjee Gouri , Huston Andrea , Kabakchiev Boyko , Piquette-Miller Micheline , van Schaik Ron , Dorfman Ruslan
Published: September 2018

Pharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support. Demystifying an often confusing and variable PGx marketplace can lead to greater acceptance of PGx as a standard-of-care practice that improves drug outcomes and provides a lifetime value for patients. Here, we highlight the key underlying factors of a PGx test that should be considered, and discuss the current progress of PGx implementation.
Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
Authors: Cao Honghui , Wang Cong , Chen Xiang , Hou Jiwei , Xiang Zou , Shen Yi , Han Xiaodong
Published: September 2018

An emerging paradigm proposes a crucial role for lung resident mesenchymal stem cells (LR-MSCs) via a fibroblastic transdifferentiation event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Aberrant activation of Wnt/β-catenin signaling occurs in virtually all fibrotic lung diseases and is relevant to the differentiation of mesenchymal stem cells (MSCs). In vitro, by measuring the protein levels of several key components involved in Wnt/β-catenin signaling, we confirmed that this signaling pathway was activated in the myofibroblast differentiation of LR-MSCs. Targeted inhibition of Wnt/β-catenin signaling by a small molecule, ICG-001, dose-dependently impeded the proliferation and transforming growth factor-β1 (TGF-β1)-mediated fibrogenic actions of LR-MSCs. In vivo, ICG-001 exerted its lung protective effects after bleomycin treatment through blocking mesenchymal-myofibroblast transition, repressing matrix gene expression, and reducing cell apoptosis. Moreover, delayed administration of ICG-001 attenuated bleomycin-induced lung fibrosis, which may present a promising therapeutic strategy for intervention of IPF. Interestingly, these antifibrotic actions of ICG-001 are operated by a mechanism independent of any disruption of Smad activation. In conclusion, our study demonstrated that Wnt/β-catenin signaling may be an essential mechanism underlying the regulation of myofibroblast differentiation of LR-MSCs and their further participation in the development of pulmonary fibrosis.
One-way Acoustic Beam Splitter
Authors: Tang Yifan , Zhu Yifan , Liang Bin , Yang Jing , Yang Jun , Cheng Jianchun
Published: September 2018

As a key component of various acoustic systems, acoustic beam splitter (BS) finds important application in many scenarios, yet are conventionally based on the assumption that the acoustic waves propagate as easily when incident from either input or output side. It would therefore be intriguing, from the viewpoints of both science and technology, to break through this limit by realizing acoustic BSs supporting asymmetric transmission. Here we propose the concept of one-way acoustic BS capable of splitting acoustic beam incident from the input port into multiple beams while effectively reducing the backward transmission from any of the output ports. Furthermore, our design enables flexibly adjusting the number and angle of output beams by blocking the unused line defects. The numerical results verify the theoretical predictions and demonstrate the phenomenon of one-way acoustic BS at the predesigned frequency. Our design with functionality and flexibility bridges the gap between acoustic diodes and BSs and may enable novel multi-functional devices with great application prospects in diverse fields such as acoustic integrated circuits and acoustic communication.
Population level mitogenomics of long-lived bats reveals dynamic heteroplasmy and challenges the Free Radical Theory of Ageing
Authors: Jebb David , Foley Nicole M. , Whelan Conor V. , Touzalin Frédéric , Puechmaille Sebastien J. , Teeling Emma C.
Published: September 2018

Bats are the only mammals capable of true, powered flight, which drives an extremely high metabolic rate. The “Free Radical Theory of Ageing” (FTRA) posits that a high metabolic rate causes mitochondrial heteroplasmy and the progressive ageing phenotype. Contrary to this, bats are the longest-lived order of mammals given their small size and high metabolic rate. To investigate if bats exhibit increased mitochondrial heteroplasmy with age, we performed targeted, deep sequencing of mitogenomes and measured point heteroplasmy in wild, long lived Myotis myotis. Blood was sampled from 195 individuals, aged between <1 and at 6+ years old, and whole mitochondria deep-sequenced, with a subset sampled over multiple years. The majority of heteroplasmies were at a low frequency and were transitions. Oxidative mutations were present in only a small number of individuals, suggesting local oxidative stress events. Cohort data showed no significant increase in heteroplasmy with age, while longitudinal data from recaptured individuals showed heteroplasmy is dynamic, and does not increase uniformly over time. We show that bats do not suffer from the predicted, inevitable increase in heteroplasmy as posited by the FRTA, instead heteroplasmy was found to be dynamic, questioning its presumed role as a primary driver of ageing.
GmGRP-like gene confers Al tolerance in Arabidopsis
Authors: Chen Li , Cai Yupeng , Liu Xiujie , Guo Chen , Yao Weiwei , Sun Shi , Wu Cunxiang , Jiang Bingjun , Han Tianfu , Hou Wensheng
Published: September 2018

Aluminium (Al) toxicity restrains water and nutrient uptake and is toxic to plant roots, ultimately inhibiting crop production. Here, we isolated and characterized a soybean glycine-rich protein-likegene (GmGRPL) that is mainly expressed in the root and that is regulated by Al treatment. Overexpression ofGmGRPLcan alleviate Al-induced root growth inhibition inArabidopsis. The levels of IAA and ethylene inGmGRPL-overexpressing hairy roots were lower than those in control and RNA interference-exposedGmGRPLhairy roots with or without Al stress, which were mainly regulated byTAA1andACO, respectively. In transgenic soybean hairy roots, the MDA, H2O2and O2–·content inGmGRPL-overexpressing hairy roots were less than that in control and RNA interference-exposedGmGRPLhairy roots under Al stress. In addition, IAA and ACC can enhance the expression level of theGmGRPLpromoter with or without Al stress. These results indicated thatGmGRPLcan alleviate Al-induced root growth inhibition by regulating the level of IAA and ethylene and improving antioxidant activity.
Variability in eukaryotic initiation factor iso4E in Brassica rapa influences interactions with the viral protein linked to the genome of Turnip mosaic virus
Authors: Li Guoliang , Qian Wei , Zhang Shujiang , Zhang Shifan , Li Fei , Zhang Hui , Fang Zhiyuan , Wu Jian , Wang Xiaowu , Sun Rifei
Published: September 2018

Plant potyviruses require eukaryotic translation initiation factors (eIFs) such as eIF4E and eIF(iso)4E to replicate and spread. When Turnip mosaic virus (TuMV) infects a host plant, its viral protein linked to the genome (VPg) needs to interact with eIF4E or eIF(iso)4E to initiate translation. TuMV utilizes BraA.eIF4E.a, BraA.eIF4E.c, BraA.eIF(iso)4E.a, and BraA.eIF(iso)4E.c of Brassica rapa to initiate translation in Arabidopsis thaliana. In this study, the BraA.eIF4E.a, BraA.eIF4E.c, BraA.eIF(iso)4E.a, and BraA.eIF(iso)4E.c genes were cloned and sequenced from eight B. rapa lines, namely, two BraA.eIF4E.a alleles, four BraA.eIF4E.c alleles, four BraA.eIF(iso)4E.a alleles, and two BraA.eIF(iso)4E.c alleles. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) analyses indicated that TuMV VPg could not interact with eIF4E, but only with eIF(iso)4E of B. rapa. In addition, the VPgs of the different TuMV isolates interacted with various eIF(iso)4E copies in B. rapa. In particular, TuMV-UK1/CDN1 VPg only interacted with BraA.eIF(iso)4E.c, not with BraA.eIF(iso)4E.a. Some single nucleotide polymorphisms (SNPs) were identified that may have affected the interaction between eIF(iso)4E and VPg such as the SNP T106C in BraA.eIF(iso)4E.c and the SNP A154C in VPg. Furthermore, a three-dimensional structural model of the BraA.eIF(iso)4E.c-1 protein was constructed to identify the specific conformation of the variable amino acids from BraA.eIF(iso)4E.c. The 36th amino acid in BraA.eIF(iso)4E.c is highly conserved and may play an important role in establishing protein structural stability. The findings of the present study may lay the foundation for future investigations on the co-evolution of TuMV and eIF(iso)4E.
Exploratory analysis of the human breast DNA methylation profile upon soymilk exposure
Authors: Coussement Louis , Bolca Selin , Van Criekinge Wim , Trooskens Geert , Mensaert Klaas , Poels Katrien , Roche Nathalie , Blondeel Phillip , Godderis Lode , Depypere Herman , De Meyer Tim
Published: September 2018

Upon soy consumption, isoflavone metabolites attain bioactive concentrations in breast tissue possibly affecting health. Though in vitro epigenetic activity of soy metabolites has been described, the in vivo impact on the epigenome is largely unknown. Therefore, in this case-control study, the breast glandular tissue DNA methylome was explored in women undergoing an aesthetic breast reduction. After a run-in phase, 10 generally healthy Belgian or Dutch women received soymilk for 5 days. MethylCap-seq methylation profiles were compared with those of 10 matched controls. Isoflavones and their microbial metabolites were quantified in urine, serum, and glandular breast tissue (liquid chromatography-mass spectrometry) and 17β-estradiol in glandular breast tissue (immunoassay). Global DNA methylation levels were obtained for 6 cases and 5 controls using liquid chromatography-mass spectrometry. Although lower MethylCap-seq coverages were observed, mass spectrometry results and computational LINE-1 methylation analysis did not provide evidence supporting global methylation alterations upon treatment. At a false discovery rate of 0.05, no differentially methylated loci were identified. Moreover, a set of previously identified loci was specifically tested, but earlier reported results could not be validated. In conclusion, after a 5-day soymilk treatment, no major general epigenetic reprogramming in breast tissue could be found in this exploratory study.
On the Stability of MHD Boundary Layer Flow over a Stretching/Shrinking Wedge
Authors: Awaludin Izyan Syazana , Ishak Anuar , Pop Ioan
Published: September 2018

The steady two dimensional magnetohydrodynamic (MHD) boundary layer flow and heat transfer over a stretching/shrinking permeable wedge is numerically investigated. The partial differential equations governing the flow and heat transfer are transformed into a system of ordinary differential equations using a similarity transformation. These equations are then solved numerically using the boundary value problem solver, bvp4c in Matlab software. It is found that dual solutions exist for a certain range of the shrinking strength. A stability analysis is performed to identify which solution is stable and physically reliable.
Ghrelin expression is associated with a favorable outcome in male breast cancer
Authors: Grönberg Malin , Nilsson Cecilia , Markholm Ida , Hedenfalk Ingrid , Blomqvist Carl , Holmberg Lars , Tiensuu Janson Eva , Fjällskog Marie-Louise
Published: September 2018

Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18–0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17–0.87). HR for obestatin was 0.38 (95% CI 0.11–1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.
Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
Authors: Florio Rosalba , De Lellis Laura , Veschi Serena , Verginelli Fabio , di Giacomo Viviana , Gallorini Marialucia , Perconti Silvia , Sanna Mario , Mariani-Costantini Renato , Natale Angelica , Arduini Arduino , Amoroso Rosa , Cataldi Amelia , Cama Alessandro
Published: September 2018

Paragangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our laboratory, we evaluated the effect of dichloroacetate (DCA) as single agent or in a novel combination with other metabolic drugs, including GW6471 and metformin. DCA and metformin had not been tested before in PGL. DCA reduced PGL cell viability and growth through mechanisms involving reactivation of PDH complex leading to promotion of oxidative metabolism, with lowering of lactate and enhanced ROS production. This resulted in cell cycle inhibition and induction of apoptosis in PGL cells, as shown by flow cytometry and immunoblot analyses. Moreover, DCA drastically impaired clonogenic activity and migration of PGL cells. Also metformin reduced PGL cell viability as single agent and the combinations of DCA, GW6471 and metformin had strong effects on cell viability. Furthermore, combined treatments had drastic and synergistic effects on clonogenic ability. In conclusion, DCA, GW6471 and metformin as single agents and in combination appear to have promising antitumor effects in unique cell models of PGL.
A carbon nanotube integrated microfluidic device for blood plasma extraction
Authors: Yeh Yin-Ting , Lin Zhong , Zheng Si-Yang , Terrones Mauricio
Published: September 2018

Blood is a complex fluid consisting of cells and plasma. Plasma contains key biomarkers essential for disease diagnosis and therapeutic monitoring. Thus, by separating plasma from the blood, it is possible to analyze these biomarkers. Conventional methods for plasma extraction involve bulky equipment, and miniaturization constitutes a key step to develop portable devices for plasma extraction. Here, we integrated nanomaterial synthesis with microfabrication, and built a microfluidic device. In particular, we designed a double-spiral channel able to perform cross-flow filtration. This channel was constructed by growing aligned carbon nanotubes (CNTs) with average inter-tubular distances of ~80 nm, which resulted in porosity values of ~93%. During blood extraction, these aligned CNTs allow smaller molecules (e.g., proteins) to pass through the channel wall, while larger molecules (e.g., cells) get blocked. Our results show that our device effectively separates plasma from blood, by trapping blood cells. We successfully recovered albumin -the most abundant protein inside plasma- with an efficiency of ~80%. This work constitutes the first report on integrating biocompatible nitrogen-doped CNT (CNxCNT) arrays to extract plasma from human blood, thus widening the bio-applications of CNTs.
Strength and Performance Enhancement of Multilayers by Spatial Tailoring of Adherend Compliance and Morphology via Multimaterial Jetting Additive Manufacturing
Authors: Ubaid Jabir , Wardle Brian L. , Kumar S.
Published: September 2018

Material tailoring of bondlayer compliance is a known effective route to enhance performance of multilayers, and here spatial material-tailoring of compliance and morphology of the adherends is examined. Multimaterial jetting additive manufacturing (AM) allows us to realize for the first time compliance- and morphology-tailored adherends, and evaluate directly the mechanical performance, including failure, of the tensile-loaded multilayers. Adherend compliance-tailoring, unlike bondlayer tailoring, requires additional consideration due to adherend bending stiffness and moment influences on bondlayer stresses. We introduce anisotropic as well as layered/sandwich adherend tailoring to address this dependence. Numerical models show that for both sub-critical and critical bondlengths (at which shear-dominated load transfer occurs through the bondlayer), adherend tailoring reduces peak stresses significantly, particularly peel stress (reductions of 47–80%) that typically controls failure in such systems. At sub-critical bondlengths, the AM-enabled layered/sandwich adherend tailoring shows significantly increased experimental performance over the baseline multilayer: strength is increased by 20%, toughness by 48%, and strain-to-break by 18%, while retaining multilayer stiffness. The adherend tailoring demonstrated here adds to the techniques available to increase the performance of bonded multilayers, suggesting that adherend tailoring is particularly well-suited to additively manufactured multilayers, but can also have application in other areas such as layered electronics and advanced structural composite laminates.
Metabolic profiling and targeted lipidomics reveals a disturbed lipid profile in mothers and fetuses with intrauterine growth restriction
Authors: Miranda Jezid , Simões Rui V. , Paules Cristina , Cañueto Daniel , Pardo-Cea Miguel A. , García-Martín María L. , Crovetto Francesca , Fuertes-Martin Rocio , Domenech Monica , Gómez-Roig María D. , Eixarch Elisenda , Estruch Ramon , Hansson Stefan R. , Amigó Nuria , Cañellas Nicolau , Crispi Fatima , Gratacós Eduard
Published: September 2018

Fetal growth may be impaired by poor placental function or maternal conditions, each of which can influence the transfer of nutrients and oxygen from the mother to the developing fetus. Large-scale studies of metabolites (metabolomics) are key to understand cellular metabolism and pathophysiology of human conditions. Herein, maternal and cord blood plasma samples were used for NMR-based metabolic fingerprinting and profiling, including analysis of the enrichment of circulating lipid classes and subclasses, as well as the number of sub-fraction particles and their size. Changes in phosphatidylcholines and glycoproteins were prominent in growth-restricted fetuses indicating significant alterations in their abundance and biophysical properties. Lipoprotein profiles showed significantly lower plasma concentrations of cholesterol-intermediate density lipoprotein (IDL), triglycerides-IDL and high-density lipoprotein (HDL) in mothers of growth-restricted fetuses compared to controls (p < 0.05). In contrast, growth-restricted fetuses had significantly higher plasma concentrations of cholesterol and triglycerides transporting lipoproteins [LDL, IDL, and VLDL, (p < 0.005; all)], as well as increased VLDL particle types (large, medium and small). Significant changes in plasma concentrations of formate, histidine, isoleucine and citrate in growth-restricted fetuses were also observed. Comprehensive metabolic profiling reveals that both, mother and fetuses of pregnancies complicated with fetal growth restriction have a substantial disruption in lipid metabolism.
Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model
Authors: Belloni Laura , Di Cocco Silvia , Guerrieri Francesca , Nunn Abigail D. G. , Piconese Silvia , Salerno Debora , Testoni Barbara , Pulito Claudio , Mori Federica , Pallocca Matteo , Sacconi Andrea , Vivoli Elisa , Marra Fabio , Strano Sabrina , Blandino Giovanni , Levrero Massimo , Pediconi Natalia
Published: September 2018

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG cells and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting.
Exploration of serum sensitive biomarkers of fatty liver in dairy cows
Authors: Shen Yizhao , Chen Lianmin , Yang Wenzhu , Wang Zhonghua
Published: September 2018

Serum proteins are sensitive with diseases in dairy cows, and some of them could be used as biomarkers for fatty liver. This study aimed to explore serum biomarkers for fatty liver in dairy cows. A total of 28 early lactating dairy cows were chosen from a commercial dairy herds, liver samples were collected for determining concentration of triacylglycerol (TAG), and serum samples were collected for measuring fibroblast growth factor-21 (FGF-21), adiponectin, Lipoprotein-associated phospholipase A2 (LP-PLA2), and hemoglobin (Hb). Dairy cows were divided into fatty liver (liver TAG > 5%, wet weight) and control group (liver TAG < 5%, wet weight). Concentration of FGF-21 was greater in fatty liver cows, while the concentration of LP-PLA2 and Hb was less. The concentration of FGF-21 and total Hb had strong correlation with the liver TAG as well as good prediction power (kappa value = 0.79 and 0.58, respectively). These results suggested that the serum concentration of FGF-21 and total Hb could be potentially used as fatty liver biomarkers in lactating dairy cows.
Seasonal consumption of polyphenol-rich fruits affects the hypothalamic leptin signaling system in a photoperiod-dependent mode
Authors: Ibars Maria , Aragonès Gerard , Ardid-Ruiz Andrea , Gibert-Ramos Albert , Arola-Arnal Anna , Suárez Manuel , Bladé Cinta
Published: September 2018

Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. The aim of this study was to investigate the effect of seasonal consumption of polyphenol-rich fruits on the hypothalamic leptin signaling system in non-obese and obese animals placed under different photoperiods. Non-obese and diet-induced obese male Fischer 344 rats were placed under either a short-day (SD) or long-day (LD) photoperiod and were supplemented with either 100 mg/kg of lyophilized red grapes or cherries. In non-obese animals, both fruits reduced energy balance independent of the photoperiod to which they were placed. However, the hypothalamic gene expression of Pomc was significantly up-regulated only in the SD photoperiod. In contrast, in obese animals only cherry significantly decreased the energy balance, although both fruits were able to counteract the diet-induced increase in hypothalamic AgRP mRNA levels when consumed during the SD photoperiod. In conclusion, the consumption of rich-polyphenol fruits may increase leptin sensitivity through the modulation of the hypothalamic leptin signal pathway mainly when consumed in the SD photoperiod. Therefore, fruit seasonality should be considered, as it can influence energy homeostasis and obesity.
Efficient modulation of subwavelength focusing via meta-aperture-based plasmonic lens for multifunction applications
Authors: Chang Kai-Hao , Chen Yen-Chun , Chang Wen-Hao , Lee Po-Tsung
Published: September 2018

Subwavelength focusing is crucial for many applications in photonics including super-resolution micro/nanoscopy, nanolithography, and optical trapping. However, most nanostructures exhibit poor ability to modulate focusing spot, which makes them hard to achieve ultra-small resolution. Here, we propose three kinds of plasmonic lens (PL) by utilizing different meta-aperture designs for efficient subwavelength focusing modulation. The shape of nanoaperture strongly influences the diffraction properties. Spatial modulation of focusing spot by employing a circular array of proposed nanoapertures is explored. The best focusing performance among these PLs is the design of T-shape nanoaperture, which has great resolution achieving ultra-small focusing spot of 0.14 λ2 and 0.20 λ2 (λ = 633 nm) for simulation and experiment respectively, better than lots of focusing devices especially by using linear polarization. Multiple-object trapping can be realized by using T-shape nanoaperture-based PL. Our designed PLs with different nanoapertures demonstrate the capability to broaden and integrate different functionalities for on-chip nanotechnologies development.
Validation of beat by beat fetal heart signals acquired from four-channel fetal phonocardiogram with fetal electrocardiogram in healthy late pregnancy
Authors: Khandoker Ahsan , Ibrahim Emad , Oshio Sayaka , Kimura Yoshitaka
Published: September 2018

Fetal heart rate monitoring is an essential obstetric procedure, however, false-positive results cause unnecessary obstetric interventions and healthcare cost. In this study, we propose a low cost and non-invasive fetal phonocardiography based signal system to measure the fetal heart sounds and fetal heart rate. Phonocardiogram (PCG) signals contain acoustic information reflecting the contraction and relaxation of the heart. We have developed a four-channel recording device with four separated piezoelectric sensors harnessed by a cloth sheet to record abdominal phonogram signals. A multi-lag covariance matrix based eigenvalue decomposition technique was used to extract fetal and maternal heart sounds as well as maternal breathing movement. In order to validate the fetal heart sounds extracted by PCG signal processing, 10 minutes’ simultaneous recordings of fetal Electrocardiogram (fECG) and abdominal phonogram from 15 pregnant women (27 ± 5-year-old) with fetal gestation ages between 33 and 40 weeks were obtained and processed. Highly significant (p < 0.01) correlation (r = 0.96; N = 270) was found between beat to beat fetal heart rate (FHRECG) from fECG and the same (FHRPCG) from fetal PCG signals. Bland–Altman plot of FHRECG and FHRPCG shows good agreement (<5% difference). We conclude that the proposed beat to beat fetal heart rate measurement system would be useful for monitoring fetal neurological wellbeing as a better alternative to traditional cardiotocogram based antenatal fetal heart rate monitoring.
Hypoxia causes reductions in birth weight by altering maternal glucose and lipid metabolism
Authors: Määttä Jenni , Sissala Niina , Dimova Elitsa Y. , Serpi Raisa , Moore Lorna G. , Koivunen Peppi
Published: September 2018

Hypoxia of residence at high altitude (>2500 m) decreases birth weight. Lower birth weight associates with infant mortality and morbidity and increased susceptibility to later-in-life cardiovascular and metabolic diseases. We sought to determine the effects of hypoxia on maternal glucose and lipid metabolism and their contributions to fetal weight. C57BL6/NCrl mice, housed throughout gestation in normobaric hypoxia (15% oxygen) or normoxia, were studied at mid (E9.5) or late gestation (E17.5). Fetal weight at E17.5 was 7% lower under hypoxia than normoxia. The hypoxic compared with normoxic dams had ~20% less gonadal white adipose tissue at mid and late gestation. The hypoxic dams had better glucose tolerance and insulin sensitivity compared with normoxic dams and failed to develop insulin resistance in late gestation. They also had increased glucagon levels. Glucose uptake to most maternal tissues was ~2-fold greater in the hypoxic than normoxic dams. The alterations in maternal metabolism in hypoxia were associated with upregulation of hypoxia-inducible factor (HIF) target genes that serve, in turn, to increase glycolytic metabolism. We conclude that environmental hypoxia alters maternal metabolism by upregulating the HIF-pathway, and suggest that interventions that antagonize such changes in metabolism in high-altitude pregnancy may be helpful for preserving fetal growth.
Evolutionary trends and phylogenetic association of key morphological traits in the Italian rice varietal landscape
Authors: Mongiano Gabriele , Titone Patrizia , Tamborini Luigi , Pilu Roberto , Bregaglio Simone
Published: September 2018

Efficient germplasm exploitation in crop breeding requires comprehensive knowledge of the available genetic diversity. Linking molecular data to phenotypic expression is fundamental for the profitable utilisation of genetic resources. Italian rice germplasm is an invaluable source of genes, being characterised by marked heterogeneity. A phenotypic characterisation is presented in this paper, with a focus on the evolutionary trends, and on the comparison with available molecular studies. A panel of 351 Italian rice varieties was analysed using seven key morphological traits, employing univariate and multivariate analyses. Considerable variability was found, with clear morphological trends towards reduced plant height, earliness, and spindle-shaped caryopses. Previous findings indicating that genetic diversity was maintained throughout time could not be confirmed, as small phenotypic variability was found in the most recent rice varieties. Consistency with phylogenetic data from previous studies was partial: one phylogenetic subgroup was phenotypically well distinct, while the others had overlapping characteristics and encompassed a wide range of phenotypic variation. Our study provides a quantitative ready-to-use set of information to support new breeding programs, as well as the basis to develop variety-specific calibrations of eco-physiological models, to identify promising traits in light of climate change conditions and alternative management scenarios.
Salt Bridge in Aqueous Solution: Strong Structural Motifs but Weak Enthalpic Effect
Authors: Pylaeva Svetlana , Brehm Martin , Sebastiani Daniel
Published: September 2018

Salt bridges are elementary motifs of protein secondary and tertiary structure and are commonly associated with structural driving force that increases stability. Often found on the interface to the solvent, they are highly susceptible to solvent–solute interactions, primarily with water but also with other cosolvents (especially ions). We have investigated the interplay of an Arginine–Aspartic acid salt bridge with simple salt ions in aqueous solution by means of molecular dynamics simulations. Besides structural and dynamical features at equilibrium, we have computed the mean force along the dissociation pathway of the salt bridge. We demonstrate that solvated ions influence the behavior of the salt bridge in a very specific and local way, namely the formation of tight ionic pairs Li+/Na+–Asp−. Moreover, our findings show that the enthalpic relevance of the salt bridge is minor, regardless of the presence of solvated ions.
Matched Short-Term Depression and Recovery Encodes Interspike Interval at a Central Synapse
Authors: Castillo Armando E. , Rossoni Sergio , Niven Jeremy E.
Published: September 2018

Reversible decreases in synaptic strength, known as short-term depression (STD), are widespread in neural circuits. Various computational roles have been attributed to STD but these tend to focus upon the initial depression rather than the subsequent recovery. We studied the role of STD and recovery at an excitatory synapse between the fast extensor tibiae (FETi) and flexor tibiae (flexor) motor neurons in the desert locust (Schistocerca gregaria) by making paired intracellular recordings in vivo. Over behaviorally relevant pre-synaptic spike frequencies, we found that this synapse undergoes matched frequency-dependent STD and recovery; higher frequency spikes that evoke stronger, faster STD also produce stronger, faster recovery. The precise matching of depression and recovery time constants at this synapse ensures that flexor excitatory post-synaptic potential (EPSP) amplitude encodes the presynaptic FETi interspike interval (ISI). Computational modelling shows that this precise matching enables the FETi-flexor synapse to linearly encode the ISI in the EPSP amplitude, a coding strategy that may be widespread in neural circuits.