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This study focused on studying the impact of flavonoids isolated from Cleome droserifolia on HCC cell lines and to further unveil their possible impact on TP53 and its downstream tumor suppressor m...

In tobacco, the efficiency of Zn translocation to shoots depends on Zn/Cd status. Previous studies pointed to the specific contribution of root parts in the regulation of this process, as well as the role of NtZIP4A/B (from the ZIP family, Zrt Irt-like Proteins). Here, to verify this hypothesis, NtZIP4A/B RNAi lines were generated. Then, in plants exposed to combinations of Zn and Cd concentrations in the medium, the consequences of NtZIP4A/B suppression for the translocation of both metals were determined. Furthermore, the apical, middle, and basal root parts were examined for accumulation of both metals, for Zn localization (using Zinpyr-1), and for modifications of the expression pattern of ZIP genes. Our results confirmed the role of NtZIP4A/B in the control of Zn/Cd-status-dependent transfer of both metals to shoots. Furthermore, they indicated that the middle and basal root parts contributed to the regulation of this process by acting as a reservoir for excess Zn and Cd. Expression studies identified several candidate ZIP genes that interact with NtZIP4A/B in the root in regulating Zn and Cd translocation to the shoot, primarily NtZIP1-like in the basal root part and NtZIP2 in the middle one.

Hexokinase catalyses hexose phosphorylation, which is the key step of sucrose metabolism. In this study, stomatal apertures of Arabidopsis epidermal peel were detected with or without exogenous application of mannose, fructose, glucose, and glucose-6-phosphate (G-6P). The results here showed that G-6P, but not glucose itself, induces stomatal closure in Arabidopsis. Furthermore, detection of stomatal apertures of Arabidopsis hexokinase loss of function with exogenous application of glucose showed that glucose induced stomatal closure was not due to osmotic pressure and it triggered guard cell ROS production depend on hexokinase activity. The effect of irradiance and G-6P on regulation of Arabidopsis stomatal aperture was investigated. The data obtained here indicated that G-6P induced changes of stomatal aperture depend on irradiance.

Although superficial scald (SS) is well characterized on apples, there is still few information regarding the influence that initial fruit’s maturity heterogeneity may have on the development of this disorder on pears. In this study we aimed to understand the effect of growing season and site, harvest maturity, and their interaction with postharvest treatments on superficial scald development. Pears (Pyrus communis L.) cv ‘Packham’s Triumph’ were picked during three consecutive seasons at three harvest maturities (H1, H2, H3) from different commercial orchards. Different SS control treatments (DPA vs. 1-MCP; season # 2) and storage scenarios (RA, CA and RA + stepwise cooling (SWC); season # 3) were evaluated. Bioclimatic indices, superficial scald incidence, maturity indices and biochemical analysis associated with SS were carried out at harvest and periodically postharvest in all treatments. In general, bioclimatic indexes (GDA and HL10) were poorly correlated with SS incidence. Only in season #1, harvest maturity was positively correlated with SS after 140 and 180 d into storage (rs = 0.621* and 0.620*, respectively), the more mature fruit being more sensitive. The opposite was observed in season #3, and no pattern in season #2. There was a good and positive correlation between CTols dynamic (δCTols/δt) and SS development, with variation between seasons. DPA and 1-MCP effectively reduced SS up to 180 d regardless of years and orchard location. In contrast, the beneficial effect of CA storage was orchard dependent and SWC strategy did not control SS and affected fruit quality. Collectively our results suggest that initial fruit heterogeneity at harvest is an important factor that modulate SS development in ‘Packham triumph pears. Climatic and fruit maturity indexes are not reliable for a multi-year prediction of SS development. In contrast to CA storage that reduced the disorder in an orchard dependent manner, 1-MCP and DPA treatments effectively controlled SS independently of initial fruit heterogeneity. info:eu-repo/semantics/acceptedVersion

Animals organize reward seeking around aversive events. An abundance of research shows that foot shock, as well as a shock-associated cue, can elicit freezing and suppress reward seeking. Yet, there is evidence that experience can flip the effect of foot shock to facilitate reward seeking. Here we examine cue suppression, foot shock suppression and foot shock facilitation of reward seeking in a single behavioural setting. Male Long Evans rats received fear discrimination consisting of danger, uncertainty and safety cues. Discrimination took place over a baseline of rewarded nose poking. With limited experience, all cues and foot shock strongly suppressed reward seeking. With continued experience, suppression became specific to shock-associated cues and foot shock facilitated reward seeking. Our results provide a means of assessing positive properties of foot shock, and may provide insight into maladaptive behavior around aversive events.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In Nigeria, tobacco snuff is the powdered form of smokeless tobacco blended with potash as its main additive. It has been discovered to have several adverse health effects, though perceived by many as safe. In this eight-week study, the effect of tobacco snuff consumption on body weight, physical observation and growth performance of Wistar rats were investigated. This study involved (42) Adult Wistar rats weighing 150-300g. They were divided into groups of tests and control, group A serving as control, while groups B, C and D of 12 Wister rats each served as the test groups. The test groups were further divided into subgroups (1, 2, 3 and 4) representing four experimental phases of 2, 4, 6 and 8 weeks respectively. The rats were fed with varying doses of tobacco snuff, while the control group (A) received feed pallets and water ad libitum. Throughout the study, serial physical and behavioural changes of the rats were recorded as well as the body weights of the rats before sacrifice. Results showed statistically significant weight changes in the test groups throughout the study period as compared with the control. On growth performance, there was an average daily growths increase in the control but decreased in the test groups in a dosage and duration dependent manner. Our findings however, indicate that tobacco snuff has the potentials of body weight reduction and could induce severe growth retardation with adversities.

INTRODUCTION Recurrent/metastatic medulloblastoma (MB) is a devastating disease with an abysmal prognosis of less than 10% 5-year survival. The secretion of extracellular vesicles (EVs) has emerged as a pivotal mediator for communication in the tumour microenvironment during metastasis. The most investigated EV’s are exosomes, nanovesicles secreted by all cell types and able to cross the blood-brain-barrier. Matrix metalloproteinases (MMPs) are enzymes secreted by tumour cells that can potentiate their dissemination by modification of the extracellular matrix. We hypothesise that exosomal MMP2 and its inducer EMMPRIN could enhance metastasis of MB. METHODS Proliferation, invasion and migration assays were used to evaluate the phenotypic behaviour of primary cell lines pre-treated with metastatic tumour cell-derived exosomes. Gelatin zymography and western blotting were performed to confirm MMP2 functional activity in cell lines and exosomes. Nanoscale flow cytometry was used to measure surface exosomal EMMPRIN levels. Exosomal MMP2 and EMMPRIN were modulated at the RNA level. RESULTS Number of exosomes is directly related to the migratory behaviour of parental MB cell lines (p CONCLUSION Together this data suggests that exosomal MMP2 and EMMPRIN may promote medulloblastoma metastasis and supports analysis of exosomal MMP2 and EMMPRIN levels in patient cerebral spinal fluid samples.

Calcification of atherosclerotic plaques in elderly patients represents a potent risk marker of cardiovascular events. Plasma analyses of patients with or without calcified plaques reveal significant differences in chemokines, particularly eotaxin, which escalates with increased calcification. We therefore, hypothesize that eotaxin in circulation augments calcification of vascular smooth muscle cells (VSMCs) possibly via oxidative stress in the vasculature. We observe that eotaxin increases the rate of calcification significantly in VSMCs as evidenced by increased alkaline phosphatase activity, calcium deposition, and osteogenic marker expression. In addition, eotaxin promotes proliferation in VSMCs and triggers oxidative stress in a NADPH oxidase dependent manner. These primary novel observations support our proposition that in the vasculature eotaxin augments mineralization. Our findings suggest that eotaxin may represent a potential therapeutic target for prevention of cardiovascular complications in the elderly. J. Cell. Biochem. 118: 647-654, 2017. © 2016 Wiley Periodicals, Inc.

Protein translocation across the bacterial cytoplasmic membrane is an essential process catalyzed predominantly by the Sec translocase. This system consists of the membrane-embedded protein-conducting channel SecYEG, the motor ATPase SecA, and the heterotrimeric SecDFyajC membrane protein complex. Previous studies suggest that anionic lipids are essential for SecA activity and that the N-terminus of SecA is capable of penetrating the lipid bilayer. The role of lipid binding, however, has remained elusive. By employing differently sized nanodiscs reconstituted with single SecYEG complexes and comprising varying amounts of lipids, we establish that SecA gains access to the SecYEG complex via a lipid-bound intermediate state, whilst acidic phospholipids allosterically activate SecA for ATP-dependent protein translocation.

AMT-L is supported by the School of Biology, University of St Andrews. AMT-L, PAR and FJGM were funded by the Anonymous Trust, University of St Andrews. PAR is supported by the Melville Trust for the Care and Cure of Cancer. The mass spectrometry work was supported by the Wellcome Trust [grant number 094476/Z/10/Z], which funded the purchase of the TripleTOF 5600 mass spectrometer at the BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews. The clinical study was supported by the Department of Pathology, Albert Einstein College of Medicine/ Montefiore Medical Center. Crumbs3 (CRB3) is a component of epithelial junctions that has been implicated in apical-basal polarity, apical identity, apical stability, cell adhesion and cell growth. CRB3 undergoes alternative splicing to yield two variants: CRB3a and CRB3b. Here, we describe novel data demonstrating that as with previous studies on CRB3a, CRB3b also promotes the formation of tight junctions. However, significantly we demonstrate that the 4.1-ezrin-radixin-moesin (FERM) binding motif (FBM) of CRB3b is required for CRB3b functionality and that ezrin binds to the FBM of CRB3b. Furthermore, we show that ezrin contributes to CRB3b functionality and the correct distribution of tight junction proteins. We demonstrate that both CRB3 isoforms are required for the production of functionally mature tight junctions and also the localization of ezrin to the plasma membrane. Finally, we demonstrate that reduced CRB3b expression in head and neck squamous cell carcinoma (HNSCC) correlates with cytoplasmic ezrin, a biomarker for aggressive disease, and show evidence that whilst CRB3a expression has no effect, low CRB3b and high cytoplasmic ezrin expression combined may be prognostic for HNSCC. Postprint

There is growing appreciation for the fundamental role of structural dynamics in the function of macromolecules. In particular, the 26S proteasome, responsible for selective protein degradation in an ATP dependent manner, exhibits dynamic conformational changes that enable substrate processing. Recent cryo-electron microscopy (cryo-EM) work has revealed the conformational dynamics of the 26S proteasome and established the function of the different conformational states. Technological advances such as direct electron detectors and image processing algorithms allowed resolving the structure of the proteasome at atomic resolution. Here we will review those studies and discuss their contribution to our understanding of proteasome function. (C) 2016 The Authors. Published by Elsevier Ltd.

Bentonite clay is widely distributed all over the world and it has been consistently used for its healing properties. In this study, the in vivo effect of natural Nigerian calcium bentonite clay on haematological parameters of wistar albino rat were investigated. The rats were fed for a total period of 28 days with varying concentrations of the bentonite clay. The haemoglobin count, packed cell volume, total white blood cell count, red blood cell count, platelet count, neutrophil and lymphocyte count were assayed. Test results showed that the bentonite had a lowering effect on haematological parameters studied in a concentration and time dependent manner with differences in concentration and time at 95 % confidence levels (P< 0.05). The highest decrease of 12.60 ± 0.36 vs control 14.35 ± 0.00 (g/dl) was obtained for Hb at the highest concentration of 0.07g at 28 days duration. PCV, WBC, RBC, platelet, neutrophil and lymphocyte analysis also showed highest decrease at 28 days duration at 0.07g/100g body weight. The results showed that using bentonite in small amounts for a short period of time had little effect. However, it is imperative that anyone intending to take large amounts of bentonite for long periods of time to undergo blood tests from time to time.

// Bing-Li Wu 1, 3, * , Dong Wang 1, 6, * , Wen-Jing Bai 1, 3 , Fan Zhang 5 , Xing Zhao 5 , Ying Yi 6 , Ting Zhang 6 , Wen-Jun Shen 5 , En-Min Li 1, 3 , Li-Yan Xu 1, 4 , Jian-Zhen Xu 1, 2, 5 1 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China 2 Computational Systems Biology Laboratory, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA 3 Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China 4 Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, China 5 Department of Bioinformatics, Shantou University Medical College, Shantou 515041, China 6 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, China * These authors have contributed equally to this work Correspondence to: En-Min Li, email: nmli@stu.edu.cn Li-Yan Xu, email: lyxu@stu.edu.cn Jian-Zhen Xu, email: xujz0451@xsgmail.com Keywords: autophagy, apoptosis, cell death, miRNA, esophageal squamous cell carcinoma Abbreviations: ESCC: esophageal squamous cell carcinoma, GO: gene ontology, SQSTM1/P62: sequestosome 1, PARP: poly (ADP-ribose) polymerase 1, LC3: microtubule-associated protein 1 light chain 3 Received: November 29, 2015 Accepted: July 06, 2016 Published: July 22, 2016 ABSTRACT Cell death is a critical biological process involved in many important functions, and defects in this system are usually linked with numerous human diseases including cancers. Esophageal squamous cell carcinoma is one of the most chemo- and biological therapy resistant cancers. Based on knowledge repository and four miRNAs profiling data, we proposed a general framework to hunt for cell death miRNAs in a context dependent manner. We predicted 12 candidate miRNAs from hundreds of others. Follow-up experimental verification of 7 miRNAs indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in both apoptosis and autophagy processes. These results indicated miRNAs intimately connected the two cell death modules in esophageal squamous cell carcinoma. This integrative framework can also be easily extended to identify miRNAs in other key cellular signaling pathways or may find conditional specific miRNAs in other cancer types.

// Xiaoxia Wang 1 , Min Cao 1,2 and Yuqing Dong 1,2 1 Department of Biological Sciences, Clemson University, Clemson, SC, USA 2 Institute for Engaged Aging, Clemson University, Clemson, SC, USA Correspondence to: Yuqing Dong, email: // Keywords : Alzheimer’s disease; royal jelly; β-amyloid; DAF-16; proteostasis; Gerotarget Received : April 21, 2016 Accepted : July 07, 2016 Published : July 26, 2016 Abstract Numerous studies have demonstrated that dietary intervention may promote health and help prevent Alzheimer’s disease (AD). We recently reported that bee products of royal jelly (RJ) and enzyme-treated royal jelly (eRJ) were potent to promote healthy aging in C. elegans . Here, we examined whether RJ/eRJ consumption may benefit to mitigate the AD symptom in the disease model of C. elegans . Our results showed that RJ/eRJ supplementation significantly delayed the body paralysis in AD worms, suggesting the β-amyloid (Aβ) toxicity attenuation effects of RJ/eRJ. Genetic analyses suggested that RJ/eRJ-mediated alleviation of Aβ toxicity in AD worms required DAF-16, rather than HSF-1 and SKN-1, in an insulin/IGF signaling dependent manner. Moreover, RJ/eRJ modulated the transactivity of DAF-16 and dramatically improved the protein solubility in aged worms. Given protein solubility is a hallmark of healthy proteostasis, our findings demonstrated that RJ/eRJ supplementation improved proteostasis, and this promotion depended on the transactivity of DAF-16. Collectively, the present study not only elucidated the possible anti-AD mechanism of RJ/eRJ, but also provided evidence from a practical point of view to shed light on the extensive correlation of proteostasis and the prevention of neurodegenerative disorders.

// Zheng Ge 1, 2, 3 , Yan Gu 2 , Lichan Xiao 2 , Qi Han 2 , Jianyong Li 2 , Baoan Chen 1 , James Yu 4 , Yuka Imamura Kawasawa 5 , Kimberly J. Payne 6 , Sinisa Dovat 3 , Chunhua Song 3 1 Department of Hematology, Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China 2 Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China 3 Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA 4 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA 5 Penn State Hershey Genome Sciences Facility, Penn State College of Medicine, Hershey, PA 17033, USA 6 Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA 92350, USA Correspondence to: Zheng Ge, email: Janege879@hotmail.com Sinisa Dovat, email: sdovat@hmc.psu.edu Chunhua Song, email: csong@hmc.psu.edu Keywords: IL7R , SH2B3 , Ikaros , gene expression, acute lymphoblastic leukemia Received: May 18, 2016 Accepted: June 03, 2016 Published: June 14, 2016 ABSTRACT Acute lymphoblastic leukemia (ALL) remains the leading cause of cancer-related death in children and young adults. Compared to ALL in children, adult ALL has a much lower cure rate. Therefore, it is important to understand the molecular mechanisms underlying high-risk ALL and to develop therapeutic strategies that specifically target genes or pathways in ALL. Here, we explored the IL7R and SH2B3 expression in adult ALL and found that IL7R is significantly higher and Sh2B3 lower expressed in B-ALL compared to normal bone marrow control, and the IL7R high SH2B3 low is associated with high-risk factors, and with high relapse rate and low disease-free survival rate in the patients. We also found that Ikaros deletion was associated with the IL7R high SH2B3 low expression pattern and Ikaros directly binds the IL7R and SH2B3 promoter, and suppresses IL7R and promotes SH2B3 expression. On the other hand, casein kinase inhibitor, which increases Ikaros function, inhibits IL7R and stimulates SH2B3 expression in an Ikaros dependent manner. Our data indicate that IL7R high SH2B3 low expression distinguishes a novel subset of high-risk B-ALL associated with Ikaros dysfunction, and also suggest the therapeutic potential for treatment that combines casein kinase inhibitor, as an Ikaros activator, with drugs that target the IL7R signaling pathway.

Gold nanoparticles demonstrate developmental toxicity in a shape dependent manner. In a zebrafish model, gold nanospheres exhibit more toxicity when compared with nanorods and nanopolyhedrons. After storage, nanopolyhedrons elicit obvious lethality. We believe that the results from this investigation could be used to track the toxicity of living organisms.

Laboratory rodents provided chronic unlimited access to running wheels display increased neurogenesis in the hippocampal dentate gyrus. In addition, recent studies indicate that such an access to wheels stimulates dendritic arborization in newly formed neurons. However, (i) the presence of the running wheel in the housing environment might also bear intrinsic influences on the number and shape of new neurons and (ii) the dendritic arborization of new neurons might be insensitive to moderate daily running activity (i.e., several hours). In keeping with these uncertainties, we have examined neurogenesis and dendritic arborization in newly formed granular cells in adult C57Bl/6N male mice housed for 3 weeks under standard conditions, with a locked wheel, with a running wheel set free 3 h/day, or with a running wheel set permanently free. The results indicate that the presence of a blocked wheel in the home cage increased cell proliferation, but not the number of new neurons while running increased in a duration-dependent manner the number of newborn neurons, as assessed by DCX labeling. Morphological analyses of the dendritic tree of newborn neurons, as identified by BrdU-DCX co-staining, revealed that although the presence of the wheel stimulated their dendritic architecture, the amplitude of this effect was lower than that elicited by running activity, and was found to be running duration-dependent.

Aims Cardiac fibroblast (CF) activation is the key event for cardiac fibrosis. The role of glycolysis and the glycolysis-related lncRNAs in CF activation are unknown. Thus, we aimed to investigate the role of glycolysis in CF activation and to identify the glycolysis-related lncRNAs involved. Main methods Glycolysis-related lncRNAs were searched and their expression profiles were validated in activated human CF (HCF) and human failing heart tissues. Expression of the target lncRNA was manipulated to determine its effects on HCF activation and glycolysis. The underlying mechanisms of lncRNA-dependent glycolysis regulation were also addressed. Key findings HCF activation induced by transforming growth factor-β1 was accompanied by an enhanced glycolysis, and 2-Deoxy- d -glucose, a specific glycolysis inhibitor, dramatically attenuated HCF activation. Twenty-eight glycolysis-related lncRNAs were identified and Linc00092 expression was changed mostly upon HCF activation. In human heart tissue, Linc00092 is primarily expressed in cardiac fibroblasts. Linc00092 knockdown activated HCFs with enhanced glycolysis, while its overexpression rescued the activated phenotype of HCFs and down-regulated glycolysis. Restoration of glycolysis abolished the anti-fibrotic effects conferred by Linc00092. Linc00092 inhibited ERK activation in activated HCFs, and ERK inhibition counteracted the fibrotic phenotype in Linc00092 knockdown HCFs. Significance These results revealed that Linc00092 could attenuate HCF activation by suppressing glycolysis. The inhibition of ERK by Linc00092 may play an important role in this process. Together, this provides a better understanding of the mechanism of CF activation and may serve as a novel target for cardiac fibrosis treatment.

Background: Radiation therapy (RT) is a mainstay of treatment for most women with breast cancer (BC). Despite this treatment, response remains heterogenous for women with estrogen receptor positive (ER+) BC. Thus, approaches that result in radiosensitization of aggressive ER+ disease are critically needed. We performed a radiosensitizer screen paired with transcriptomic and proteomic data from ER+ models treated +/-RT to identify potential mediators of RT resistance. Methods: Clonogenic survival assays were used to determine RT sensitivity of 21 BCC lines as well as radiosensitization with drug treatment. IC50 values were determined for 130 clinical compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Microarray and RPPA data was used for differential gene/protein expression and pathway analysis. AlamarBlue was used to determine IC50 values of the MDM2 inhibitor AMG-232. Western blot analysis of Cleaved PARP was used to measure apoptosis and Cyclins A and E to measure cell cycle progression. Results: Our radiosensitizer screen nominated the MDM2 inhibitor (JNJ-26854165) as one of the most effective drugs in treating RT-resistant BC cell lines (R2= 0.43, p-value 10uM). Clonogenic survival assays demonstrated that MDM2 inhibition at sub-IC50 doses leads to radiosensitization in p53 WT ER+ cell lines (MCF-7 rER: 1.37-1.66;ZR751 rER: 1.30-1.65). In contrast, p53 MT ER+ cells did not demonstrate significant radiosensitization (T47D rER: 0.94-1.11). Combination of AMG-232 and RT led to an increase in apoptosis compared to RT alone in ER+ p53 WT cells but not p53 MT cells. Additionally, combination treatment led to differential cylin expression in p53 WT cells but not p53 MT cells. In vivo studies testing MDM2 inhibition with RT in p53 WT and MT orthotopic and PDX models are ongoing. Conclusions: Our novel radiosensitizer screen identifies MDM2 as a potential mediator of radioresistance in ER+ BC. Additionally, MDM2 inhibition confers radiosensitization in a p53 dependent manner in ER+ BC and may represent a tractable clinical strategy in women with p53 WT BC. Citation Format: Cassandra L. Ritter, Benjamin C. Chandler, Andrea M. Pesch, Anna R. Michmerhuizen, Nicole Hirsh, Amanda Zhang, Tanner Ward, Mattia Cremona, Bryan Hennessy, Lori J. Pierce, Corey W. Speers. A radiosensitizer screen identifies a novel role for MDM2 inhibition in the radiosensitization of ER+ breast cancers in a p53 dependent manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6270.

Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles located in the surrounding stroma. It is a pathological feature observed in certain tumors, referred to as neurotropic malignancies, that severely limits the ability to establish local control of disease and results in pain, recurrent growth, and distant metastases. Despite the importance of PNI as a prognostic indicator, its biological mechanisms are poorly understood. The semaphorins and their receptors, the plexins, compose a family of proteins originally shown to be important in nerve cell adhesion, axon migration, and proper central nervous system development. Emerging evidence has demonstrated that these factors are expressed in tissues outside of the nervous system and represent a widespread signal transduction system that is involved in the regulation of motility and adhesion in different cell types. We believe that the plexins and semaphorins, which are strongly expressed in both axons and many carcinomas, play a role in PNI. In this study, we show that plexin-B1 is overexpressed in tissues and cell lines from neurotropic malignancies and is attracted to nerves that express its ligand, semaphorin 4D, in a Rho/Rho kinase-dependent manner. We also demonstrate that nerves are attracted to tumors through this same system of proteins, suggesting that both plexin-B1 and semaphorin 4D are important in the promotion of PNI.

The expansion of adipose tissue increases leptin secretion associated with a reduction of adiponectin concentration, which negatively affects health of adolescents with obesity. This study aims to investigate the effects of non-intensive interdisciplinary therapy on cardiometabolic parameters including leptin, adiponectin and adiponectin/leptin ratio as a dependent manner on its magnitude of weight loss reduction.Thirty-eight adolescents (14-19 y.o) were enrolled in an interdisciplinary therapy for 20 weeks. Body composition, biochemical parameters, leptin and adiponectin were measured at baseline and after therapy. The adolescents were divided into two groups according to the magnitude of total weight loss, less than 5% (5%-n = 18) or greater than or equal to 5% (≥5%-n = 20). Leptin decreased in whole group after therapy, while adiponectin, and adiponectin/leptin ratio increased. Additionally, body composition was improved. Only the group who lost ≥5% of body weight could reduce the inflammatory state.The interdisciplinary therapy contributes to improve cardiometabolic parameters that could be involved on inflammation in adolescents with obesity, this improvement occurred mainly when the weight loss is ≥5% of body weight. It could be a target for control the inflammatory process related to obesity in adolescents.

There is fast increasing interest in the development of food grade high internal phase emulsions (HIPEs; with oil fractions > 0.74) stabilized by protein-based particles, due to their potential applications in food, cosmetics and biomedical fields. This work reported that soy glycinin (SG), an important soy storage globulin, exhibited a potential to act as Pickering stabilizers for HIPEs; and the glycation with soy soluble polysaccharide (SSPS) greatly improved the emulsification performance of SG, the gel network formation and stability (against heating or freeze-thawing) of the resultant HIPEs. In the work, two selected glycation incubation periods (24 and 72 h) were applied to obtain the glycated SG. The results indicated that the glycation progressively decreased the minimal concentration required for the formation of gel-like HIPEs, and droplet size, but increased the gel network strength, in an incubation period dependent manner. The improvement of emulsification performance by the glycation was mainly associated with the enhanced adsorption, as well as facilitated subunit dissociation at the interface, during the HIPE formation. All the HIPEs stabilized by untreated or glycated SG exhibited an excellent coalescence stability against a long-term storage. The structural analyses of non-adsorbed and adsorbed SG indicated that although untreated SG showed a high whole structural integrity with no distinct changes in structures after adsorption at interface, it tended to aggregate (due to its high surface hydrophobicity); in contrast, glycated SG easily dissociated into subunits at the interface, but the dissociated subunits exhibited a high structural stability at the tertiary and secondary levels. The findings would be of importance not only for the development of soy protein-based Pickering stabilizers for emulsions or HIPEs, but also for extending the knowledge about the modification of emulsifying properties of proteins by glycation with carbohydrates.

Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in preterm infants. Formula feeding is a risk factor for NEC and osmolality, which is increased by the fortification that is required for adequate growth of the infant, has been suggested as a potential cause. Our laboratory has shown that Paneth cell disruption followed by induction of dysbiosis can induce NEC-like pathology in the absence of feeds. We hypothesized adding formula feeds to the model would exacerbate intestinal injury and inflammation in an osmolality-dependent manner. NEC-like injury was induced in 14&ndash, 16 day-old C57Bl/6J mice by Paneth cell disruption with dithizone or diphtheria toxin, followed by feeding rodent milk substitute with varying osmolality (250&ndash, 1491 mOsm/kg H2O). Animal weight, serum cytokines and osmolality, small intestinal injury, and cecal microbial composition were quantified. Paneth cell-disrupted mice fed formula had significant NEC scores compared to controls and no longer required induction of bacterial dysbiosis. Significant increases in serum inflammatory markers, small intestinal damage, and overall mortality were osmolality-dependent and not related to microbial changes. Overall, formula feeding in combination with Paneth cell disruption induced NEC-like injury in an osmolality-dependent manner, emphasizing the importance of vigilance in designing preterm infant feeds.

Three months of exercise training (ET) decreases soluble A&beta, 40 and A&beta, 42 levels in an intensity dependent manner early in life in Tg2576 mice (Moore et al., 2016). Here, we examined the effects of 12 months of low- and high- intensity exercise training on cognitive function and amyloid plaque load in the cortex and hippocampus of 15-month-old Tg2576 mice. Low- (LOW) and high- (HI) intensity ET animals ran at speeds of 15 m/min on a level treadmill and 32 m/min at a 10% grade, respectively, for 60 min/day, five days/week, from 3 to 15 months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. ET mice demonstrated a significantly lower amyloid plaque load in the cortex and hippocampus that was intensity dependent. Improvement in cognitive function, assessed by Morris Water Maze and Novel Object Recognition tests, was greater in the HI group compared to the LOW and SED groups. LOW mice performed better in the initial latency to the platform location during the probe trial of the Morris Water Maze (MWM) test than SED, but not in any other aspect of MWM or the Novel Object Recognition test. The results of this study indicate that exercise training decreases amyloid plaque load in an intensity dependent manner and that high-intensity exercise training improves cognitive function relative to SED mice, but the intensity of the LOW group was below the threshold to demonstrate robust improvement in cognitive function in Tg2576 mice.

Methamphetamine (MA), a synthetic derivate of amphetamine, has become a major drug of abuse worldwide. This study investigated the effect of binge-like MA dosing (4 x 4 mg/kg, s.c., 2 h (h) apart) at a range of different time points (from 2 h to 7 days after treatment) on brain-derived neurotrophic factor (BDNF) levels and its receptors, TrkB and p75NTR. BDNF levels were significantly increased in the frontal cortex from 2 to 36 h after treatment, returning to normal within 48 h after treatment. In the striatum, BDNF expression was increased at 12 and 24 h after binge-like MA treatment and had returned to normal at 36 h. Increased expression of the TrkB receptor was observed in the frontal cortex at 2, 24 and 48 h after MA treatment and in the striatum at 24 and 48 h after the MA regimen. A significant increase in the p75NTR receptor was also noted in the striatum but not the frontal cortex, and it was less pronounced than the effect on TrkB receptor expression. These findings show that the binge-like regimen of MA affects expression of BDNF and its receptors, particularly the TrkB receptor, in a time and region dependent manner, and highlights the importance of the frontal cortex and the striatum in the response following MA binge-like dosing. This research was funded by a College of Science Scholarship, National University of Ireland, Galway. The authors acknowledge the contribution of Prof. Afshin Samali, School of Natural Sciences, NUI Galway, to this study. The authors acknowledge the facilities and scientific and technical assistance of the Centre for Microscopy & Imaging at the National University of Ireland Galway peer-reviewed 2020-11-03

This study evaluates the liver toxicity of three different herbal bitters (G. Winco, 1960 roots and Confam) on Wister albino rats. A total of 40 rats were randomly divided into 4 groups labeled A, B, C and D and kept in a well ventilated room. Group A served as control and these rats were treated with distilled water. Wister albino rats in the groups B, C and D were treated with 3 different doses of the bitters (20, 30 and 40mL/Kgbw) respectively. The drugs were administered once daily for 10 and 21days consecutively. Animals were sacrificed 24 hours after the last treatment. Blood samples were collected into heparinized sample bottles for analysis. There was no significant difference in the results obtained. Alkaline phosphatase and aspartate transaminase was decreased in a non-dose dependent manner in this study. Alanine transaminase was elevated in a dose dependent manner. Histopathological changes were seen in all doses and duration of administration of confam. 1960 roots showed these changes with increasing duration of use and doses. These results further suggest that these bitters cause some degree of hepatic damage and should be used with care, in moderate amounts and with proper monitoring of liver function indices.

On cell-membrane surfaces, receptor-protein dimers play fundamental roles in many signaling pathways that are crucial for normal biological processes and cancer development. Efficient and sensitive analysis of receptor dimers in the native environment is highly desirable. Herein, we present a strategy for amplified imaging of receptor dimers in zebrafish and living cells that relies on aptamer recognition and proximity-induced hybridization chain reaction. Taking advantage of specific aptamer recognition and enzyme-free signal amplification, this strategy is successfully applied to the visualization of c-Met-receptor dimers in an HGF-independent or -dependent manner. Therefore, the developed imaging strategy paves the way for further investigation of the dimerization or oligomerization states of cell-surface receptors and their corresponding activation processes in zebrafish and living cells.

The role of OPA1-related mitochondrial fusion in cardiac reperfusion stress has remained elusive. The aim of our study is to explore whether melatonin alleviates cardiac ischemia-reperfusion (IR) injury by modulating OPA1-related mitochondrial fusion. We found that melatonin reduced infarct area, sustained myocardial function, and suppressed cardiomyocyte death during cardiac reperfusion stress. Biological studies have revealed that IR-inhibited mitochondrial fusion was largely reversed by melatonin through upregulated OPA1 expression. Knocking down OPA1 abrogated the protective effects of melatonin on mitochondrial energy metabolism and mitochondrial apoptosis. In addition, we also found that melatonin modified OPA1 expression through the Yap-Hippo pathway; blockade of the Yap-Hippo pathway induced cardiomyocyte death and mitochondrial damage despite treatment with melatonin. Altogether, our data demonstrated that cardiac IR injury is closely associated with defective OPA1-related mitochondrial fusion. Melatonin supplementation enhances OPA1-related mitochondrial fusion by activating the Yap-Hippo pathway, ultimately reducing cardiac reperfusion stress.

Tamoxifen, a selective estrogen receptor modulator, is widely used in mouse models to temporally control gene expression but is also known to affect body composition. Here, we report that tamoxifen has significant and sustained effects on glucose tolerance, independent of effects on insulin sensitivity, in mice. Intraperitoneal, but not oral, tamoxifen delivery improved glucose tolerance in three inbred mouse strains. The extent and persistence of tamoxifen-induced effects were sex- and strain-dependent. These findings highlight the need to revise commonly used tamoxifen-based protocols for gene manipulation in mice by including longer chase periods following injection, oral delivery, and the use of tamoxifen-treated littermate controls.

Glioblastoma (GBM) is a malignant primary brain cancer without cure, due to the edge infiltrating tumor cells and non-complete resection. Although intratumoral heterogeneity is recognized in various cancers including GBM, its spatial distribution and intercellular crosstalk remain poorly understood. Previously, we identified two mutually exclusive glioma stem-like cells (GSCs) subtypes in GBM, termed mesenchymal (MES) and non-MES GSCs. Here, we tested the hypothesis that non-MES and MES GSCs have inter-cellular crosstalk to promote GBM aggressiveness and heterogeneity. We found that MES GSCs are preferentially located in the tumor core region, while non-MES GSCs subside in the tumor edge. Co-culture with MES GSC-containing cultures (glioma spheres) promoted both in vitro growth and in vivo tumorigenicity of non-MES ones. By a high throughput screening, several HDAC inhibitors selectively eliminated MES glioma spheres, while preserving non-MES glioma spheres. Among the HDAC family, HDAC1 is upregulated in GBM and associated with unfavorable outcome. Knockdown of HDAC1 blocked the intercellular pro-tumorigenic signal from MES glioma spheres to the non-MES counterparts. Mechanistically, CD109 is secreted from MES glioma spheres, thereby contributing intercellular pro-tumorigenic signals from MES to non-MES spheres. By RNA sequence, we found that HDAC1 regulates transcriptional activity of CD109 via binding to the promoter of CD109 together with the MES-specific transcription factor C/EBPb. To validate the intercellular signals in a single tumor, we established 6 clones of spheres from both tumor core and edge derived from the same GBM patient. The core lines contained those with higher resistance to irradiation (IR) treatment in comparison to the edge-derived counterparts. Furthermore, the core glioma spheres that showed higher MES signature promoted the growth and transformation of the non-MES like edge-derived glioma spheres both in vitro and in vivo. Collectively, our data identified HDAC1-CD109 dependent intercellular crosstalk from core like MES GCSs to edge like non-MES GSCs.

Pizzinga et al. show that mRNAs encoding a range of translation factors are localized to granules that get transported into the yeast daughter cell using the She2p/She3p machinery. This likely supports an intensification of protein synthetic activity to facilitate apical polarized growth., mRNA localization serves key functions in localized protein production, making it critical that the translation machinery itself is present at these locations. Here we show that translation factor mRNAs are localized to distinct granules within yeast cells. In contrast to many messenger RNP granules, such as processing bodies and stress granules, which contain translationally repressed mRNAs, these granules harbor translated mRNAs under active growth conditions. The granules require Pab1p for their integrity and are inherited by developing daughter cells in a She2p/She3p-dependent manner. These results point to a model where roughly half the mRNA for certain translation factors is specifically directed in granules or translation factories toward the tip of the developing daughter cell, where protein synthesis is most heavily required, which has particular implications for filamentous forms of growth. Such a feedforward mechanism would ensure adequate provision of the translation machinery where it is to be needed most over the coming growth cycle.