bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostaglandin E1 Attenuates Pulmonary Artery Remodeling by Activating Phosphorylation of CREB and the PTEN Signaling Pathway
Authors: Lai Ying-Ju , Hsu Hsao-Hsun , Chang Gwo-Jyh , Lin Shu-Hui , Chen Wei-Jan , Huang Chung-Chi , Pang Jong-Hwei S.
Published: August 2017

The depletion of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and phosphatase and tensin homolog (PTEN) is the critical mediator of pulmonary arterial hypertension (PAH). We hypothesized that the activation of phosphorylated CREB (pCREB) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline-induced PAH. We observed decreased PTEN and pCREB in idiopathic PAH versus control tissue. We reduced PTEN using small interfering RNA in human control pulmonary arterial smooth muscle cells (PASMCs) and observed an increase in pAKT. Consistent with PTEN knockdown in PASMCs, prostaglandin E1 (PGE1) induced pCREB expression to stimulate PTEN protein expression and inhibited pAKT in a time- and dose-dependent manner. The enhanced proliferation and migration of PASMCs following PTEN knockdown were significantly inhibited by PGE1 treatment. The PGE1-induced elevation of PTEN expression in PTEN-depleted PASMCs was decreased by the application of a PKA inhibitor and a CBP-CREB interaction inhibitor. Supplementation with a novel emulsion composition comprising PGE1 in rats with monocrotaline-induced PAH prevented pulmonary arterial remodeling and improved hemodynamics via the induced expression of PTEN. We conclude that PGE1 recruits pCREB/PTEN to decrease the migration and proliferation of PASMCs associated with PAH. This finding elucidates a relevant underlying mechanism of the PGE1/CREB/PTEN signaling pathway to prevent progressive PAH.
Regulation of focal adhesion turnover in SDF-1α-stimulated migration of mesenchymal stem cells in neural differentiation
Authors: Hu Ya’nan , Lu Junhou , Xu Xiaojing , Lyu Jingya , Zhang Huanxiang
Published: August 2017

Directed migration of the transplanted mesenchymal stem cells (MSCs) to the lesion sites plays a pivotal role in the efficacy of cell-based therapy. Our previous study demonstrates that MSCs under varying neural differentiation states possess different migratory capacities in response to chemoattractants. However, the underlying mechanism has not been fully addressed. Herein, we show that the assembly and turnover of focal adhesions, the phosphorylation of FAK and paxillin, and the reorganisation of F-actin in MSCs are closely related to their differentiation states in response to SDF-1α. Upon SDF-1α stimulation, FAs turnover more rapidly with the most obvious reduction in the existing time of FAs in MSCs of 24-h preinduction that exhibit the most effective migration towards SDF-1α. Further, we confirm that PI3K/Akt and MAPK pathways participate in the regulation of SDF-1α-induced cell migration and FA assembly, and moreover, that the regulatory effects vary greatly depending on the differentiation states. Collectively, these results demonstrate that FA assembly and turnover, which is accompanied with F-actin reorganisation in response to SDF-1α, correlates closely with the differentiation states of MSCs, which might contribute to the different chemotactic responses of these cells, and thus help develop new strategy to improve the efficacy of MSCs-based therapy.
Contamination-free graphene by chemical vapor deposition in quartz furnaces
Authors: Lisi Nicola , Dikonimos Theodoros , Buonocore Francesco , Pittori Martina , Mazzaro Raffaello , Rizzoli Rita , Marras Sergio , Capasso Andrea
Published: August 2017

Although the growth of graphene by chemical vapor deposition is a production technique that guarantees high crystallinity and superior electronic properties on large areas, it is still a challenge for manufacturers to efficiently scale up the production to the industrial scale. In this context, issues related to the purity and reproducibility of the graphene batches exist and need to be tackled. When graphene is grown in quartz furnaces, in particular, it is common to end up with samples contaminated by heterogeneous particles, which alter the growth mechanism and affect graphene’s properties. In this paper, we fully unveil the source of such contaminations and explain how they create during the growth process. We further propose a modification of the widely used quartz furnace configuration to fully suppress the sample contamination and obtain identical and clean graphene batches on large areas.
Multicentre evaluation of the BYG Carba v2.0 test, a simplified electrochemical assay for the rapid laboratory detection of carbapenemase-producing Enterobacteriaceae
Authors: Bogaerts Pierre , Oueslati Saoussen , Meunier Danièle , Nonhoff Claire , Yunus Sami , Massart Marion , Denis Olivier , Woodford Neil , Hopkins Katie L. , Naas Thierry , Dortet Laurent , Huang Te-Din , Glupczynski Youri
Published: August 2017

Rapid detection of carbapenemase-producing Enterobacteriaceae (CPE) represents a major challenge for microbiology laboratories. We evaluated the BYG Carba v2.0 using a simplified protocol, which detects CPE in less than 30 minutes. This new procedure reduces the hands-on-time from 5 to one minute and only requires a limited amount of material (one to three colonies) thereby preventing the need for subculturing bacterial isolates to reach a larger amount of pure biomass. This multicentre study involved four European reference laboratories. For the 1181 isolates tested across four centres, BYG Carba v2.0 yielded overall sensitivity and specificity of 96.3% (CI95: 94.5–97.5) and 99.7% (CI95: 98.6–100) respectively. Considering only the 670 consecutive isolates tested prospectively, the BYG Carba v2.0 displayed overall positive and negative predictive values of 99.7% (CI95: 95.4–98.9) and 97.5% (CI95: 94.9–98.8). Regarding time to positivity, 85% of CPE detected were positive within ten minutes. The BYG Carba v2.0 is a new highly simplified, rapid and accurate electrochemical assay discriminating between CPE and non-CPE in less than 30 min. The real-time quantified signal allows objective and traceable interpretation of the results.
Nonalcoholic Fatty Liver Disease and Coronary Artery Calcification in a Northern Chinese Population: a Cross Sectional Study
Authors: Wu Rina , Hou Feng , Wang Xiaomin , Zhou Yong , Sun Kai , Wang Youxin , Liu Henghui , Wu Jing , Zhao Ruiping , Hu Jiang
Published: August 2017

Nonalcoholic fatty liver disease (NAFLD) has become an emerging health issue with a high prevalence in general population. The cross-sectional study was performed to investigate the association between NAFLD and coronary artery calcification (CAC) in individuals from northern city of China. A total of 2345 participants aged ≥40 (1035 men and 1310 women) were selected from the Jidong community of Tangshan city. Liver ultrasonography was used to the diagnosis of NAFLD. A 64-slice CT scanner was used to determine coronary artery calcification score (CACS), with CACS > 0 defined to be the presence of CAC. The risk level of coronary heart disease (CHD) was graded by CACS according to the 4 commonly used thresholds in clinical practice (0, 10, 100, and 400 Agatston units). NAFLD was significantly associated with CAC (crude OR: 1.631, 95% CI: 1.295–2.053, adjusted OR: 1.348, 95% CI: 1.030–1.765). The association between NAFLD and increased risk level of CHD (Crude OR: 1.639 95% CI: 1.303–2.063; adjusted OR: 1.359 95% CI: 1.043–1.770) was observed. The associations between NAFLD and CAC or increased risk level of CHD were significant in female but not in male. Our finding further confirmed the association between NAFLD and CAC, especially in Asian population.
Altered cross-talk between the hypothalamus and non-homeostatic regions linked to obesity and difficulty to lose weight
Authors: Contreras-Rodríguez Oren , Vilar-López Raquel , Andrews Zane B. , Navas Juan F , Soriano-Mas Carles , Verdejo-García Antonio
Published: August 2017

Interactions between the hypothalamus and non-homeostatic regions may contribute to explain the difficulty to lose weight in obesity, an assumption never tested in human longitudinal studies. We investigated whether the functional connectivity between the medial and lateral hypothalamus (MH and LH) and corticostriatal regions differs between individuals with excess weight (n = 42) and normal weight (n = 39) using a seed-based resting-state approach. In addition, we examined the longitudinal association between functional connectivity and weight loss in a 3-month follow-up diet. Results showed that participants with excess weight had increased connectivity between the MH and the striatum and subgenual anterior cingulate cortex, and decreased connectivity with the middle frontal gyrus, and the bed nucleus of the stria terminalis (BNST), as well as a decreased connectivity between the LH and the cerebellum. Decreased connectivity between the MH and the posterior part of the BNST, and between the LH and the cerebellar cortex, predicted a greater percentage of weight loss. Functional connectivity measures explained 36% of the 3-month weight change among individuals with excess weight. We conclude that altered functional connectivity between homeostatic-hypothalamic regions and non-homeostatic corticostriatal and cerebellar regions is linked to obesity and difficulty to lose weight.
Spontaneous establishing of cross-modal stimulus equivalence in a beluga whale
Authors: Murayama Tsukasa , Suzuki Ryota , Kondo Yurika , Koshikawa Mana , Katsumata Hiroshi , Arai Kazutoshi
Published: August 2017

Beluga whales use calls to convey various information to group members. Is this communication similar to humans? We addressed this question by using the framework of stimulus equivalence. Stimulus equivalence consists of three phases: if the animal is trained to match A to B and B to C, symmetry is demonstrated by matching BA and CB, transitivity by matching AC, and equivalence by matching CA. We tested the spontaneous establishment of cross-modal stimulus equivalence between visual and auditory symbols in a beluga whale nicknamed Nack. Nack could make symmetrical choices in novel objects untrained. Moreover, visual/auditory cross-modal transitivity was formed spontaneously. Nack succeeded in six tasks, including an untrained task concerning stimulus equivalence. We conclude that Nack spontaneously formed cross-modal stimulus equivalence between visual and auditory symbols. Cross-modal stimulus equivalence was considered to exist only in humans because of linguistic faculty; however, Nack exhibited the same understanding as humans.
Continuous coloured light altered human brain haemodynamics and oxygenation assessed by systemic physiology augmented functional near-infrared spectroscopy
Authors: Metz A. J. , Klein S. D. , Scholkmann F. , Wolf U.
Published: August 2017

Exposure to artificial coloured light is unavoidable in our modern life, but we are only just beginning to understand the impact of coloured light on human physiology. The aim of the present study was to determine effects of coloured light exposure on human systemic and brain physiology using systemic physiology augmented functional near-infrared spectroscopy (SPA-fNIRS). We measured changes in haemoglobin concentrations and tissue oxygen saturation in the left and right prefrontal cortices (L-PFC, R-PFC) by fNIRS, and also recorded skin conductance (SC), partial pressure of end-tidal CO2 (PETCO2), and heart-rate variability variables. 17 healthy adults (median age: 29 years, range: 25–65 years, 6 women) were exposed to blue, red, green, or yellow light for 10 minutes. Pre-light and post-light conditions were in darkness. In the L-PFC the yellow evoked a brain activation. SC and PETCO2 did not change during any of the coloured light exposures, but SC increased and PETCO2 decreased for all colours (except green) in the post-light period. Changes in L-PFC haemoglobin concentration were also observed during the post-light period but have to be interpreted with care, because heart rate and SC increased while PETCO2 decreased. The detected effects are potentially of high relevance for choosing room lighting and may possibly be applied therapeutically.
Diverse Functionalities of Vertically Stacked Graphene/Single layer n-MoS2/SiO2/p-GaN Heterostructures
Authors: Perumal Packiyaraj , Karuppiah Chelladurai , Liao Wei-Cheng , Liou Yi-Rou , Liao Yu-Ming , Chen Yang-Fang
Published: August 2017

Integrating different dimentional materials on vertically stacked p-n hetero-junctions have facinated a considerable scrunity and can open up excellent feasibility with various functionalities in opto-electronic devices. Here, we demonstrate that vertically stacked p-GaN/SiO2/n-MoS2/Graphene heterostructures enable to exhibit prominent dual opto-electronic characteristics, including efficient photo-detection and light emission, which represents the emergence of a new class of devices. The photoresponsivity was found to achieve as high as ~10.4 AW−1 and the detectivity and external quantum efficiency were estimated to be 1.1 × 1010 Jones and ~30%, respectively. These values are superier than most reported hererojunction devices. In addition, this device exhibits as a self-powered photodetector, showing a high responsivity and fast response speed. Moreover, the device demonstrates the light emission with low turn-on voltage (~1.0 V) which can be realized by electron injection from graphene electrode and holes from GaN film into monolayer MoS2 layer. These results indicate that with a suitable choice of band alignment, the vertical stacking of materials with different dimentionalities could be significant potential for integration of highly efficient heterostructures and open up feasible pathways towards integrated nanoscale multi-functional optoelectronic devices for a variety of applications.
Structural and Functional View of Polypharmacology
Authors: Moya-García Aurelio , Adeyelu Tolulope , Kruger Felix A. , Dawson Natalie L. , Lees Jon G. , Overington John P. , Orengo Christine , Ranea Juan A. G.
Published: August 2017

Protein domains mediate drug-protein interactions and this principle can guide the design of multi-target drugs i.e. polypharmacology. In this study, we associate multi-target drugs with CATH functional families through the overrepresentation of targets of those drugs in CATH functional families. Thus, we identify CATH functional families that are currently enriched in drugs (druggable CATH functional families) and we use the network properties of these druggable protein families to analyse their association with drug side effects. Analysis of selected druggable CATH functional families, enriched in drug targets, show that relatives exhibit highly conserved drug binding sites. Furthermore, relatives within druggable CATH functional families occupy central positions in a human protein functional network, cluster together forming network neighbourhoods and are less likely to be within proteins associated with drug side effects. Our results demonstrate that CATH functional families can be used to identify drug-target interactions, opening a new research direction in target identification.
Micro-hydrogel Particles Consisting of Hyperbranched Polyamidoamine for the Removal of Heavy Metal Ions from Water
Authors: Lee Sanghwa , Eom Youngsik , Park Jeyoung , Lee Jinhee , Kim Sang Youl
Published: August 2017

A series of micro-hydrogel particles consisting of hyperbranched polyamidoamine (HPAMAM) without any supporting core materials was synthesized via the inverse suspension condensation polymerization of A2and B4monomers,N,N′-methylenebisacrylamide (MBA) and ethylenediamine (EDA). The particles were found to be highly effective when used to remove heavy metal ions, such as cadmium, copper, lead, nickel, zinc, and cobalt, from water, and they could be separated from the water by a simple filtration process. The results of this study demonstrate that crosslinked HPAMAM particles, which can be prepared by a simple and environmentally friendly process, are an attractive absorbent for water purification.
Developmentally Regulated GTP binding protein 1 (DRG1) controls microtubule dynamics
Authors: Schellhaus Anna Katharina , Moreno-Andrés Daniel , Chugh Mayank , Yokoyama Hideki , Moschopoulou Athina , De Suman , Bono Fulvia , Hipp Katharina , Schäffer Erik , Antonin Wolfram
Published: August 2017

The mitotic spindle, essential for segregating the sister chromatids into the two evolving daughter cells, is composed of highly dynamic cytoskeletal filaments, the microtubules. The dynamics of microtubules are regulated by numerous microtubule associated proteins. We identify here Developmentally regulated GTP binding protein 1 (DRG1) as a microtubule binding protein with diverse microtubule-associated functions. In vitro, DRG1 can diffuse on microtubules, promote their polymerization, drive microtubule formation into bundles, and stabilize microtubules. HeLa cells with reduced DRG1 levels show delayed progression from prophase to anaphase because spindle formation is slowed down. To perform its microtubule-associated functions, DRG1, although being a GTPase, does not require GTP hydrolysis. However, all domains are required as truncated versions show none of the mentioned activities besides microtubule binding.
Synchronized Activity in The Main and Accessory Olfactory Bulbs and Vomeronasal Amygdala Elicited by Chemical Signals in Freely Behaving Mice
Authors: Pardo-Bellver Cecília , Martínez-Bellver Sergio , Martínez-García Fernando , Lanuza Enrique , Teruel-Martí Vicent
Published: August 2017

Chemosensory processing in mammals involves the olfactory and vomeronasal systems, but how the activity of both circuits is integrated is unknown. In our study, we recorded the electrophysiological activity in the olfactory bulbs and the vomeronasal amygdala in freely behaving mice exploring a battery of neutral and conspecific stimuli. The exploration of stimuli, including a neutral stimulus, induced synchronic activity in the olfactory bulbs characterized by a dominant theta rhythmicity, with specific theta-gamma coupling, distinguishing between vomeronasal and olfactory structures. The correlated activation of the bulbs suggests a coupling between the stimuli internalization in the nasal cavity and the vomeronasal pumping. In the amygdala, male stimuli are preferentially processed in the medial nucleus, whereas female cues induced a differential response in the posteromedial cortical amygdala. Thus, particular theta-gamma patterns in the olfactory network modulates the integration of chemosensory information in the amygdala, allowing the selection of an appropriate behaviour.
Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers
Authors: Altmäe Signe , Koel Mariann , Võsa Urmo , Adler Priit , Suhorutšenko Marina , Laisk-Podar Triin , Kukushkina Viktorija , Saare Merli , Velthut-Meikas Agne , Krjutškov Kaarel , Aghajanova Lusine , Lalitkumar Parameswaran G. , Gemzell-Danielsson Kristina , Giudice Linda , Simón Carlos , Salumets Andres
Published: August 2017

Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from ‘pre-receptive’ and 88 from mid-secretory, ‘receptive’ phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.
Global associations between regional gray matter volume and diverse complex cognitive functions: evidence from a large sample study
Authors: Takeuchi Hikaru , Taki Yasuyuki , Nouchi Rui , Yokoyama Ryoichi , Kotozaki Yuka , Nakagawa Seishu , Sekiguchi Atsushi , Iizuka Kunio , Yamamoto Yuki , Hanawa Sugiko , Araki Tsuyoshi , Miyauchi Carlos Makoto , Shinada Takamitsu , Sakaki Kohei , Sassa Yuko , Nozawa Takayuki , Ikeda Shigeyuki , Yokota Susumu , Daniele Magistro , Kawashima Ryuta
Published: August 2017

Correlations between regional gray matter volume (rGMV) and psychometric test scores have been measured to investigate the neural bases for individual differences in complex cognitive abilities (CCAs). However, such studies have yielded different rGMV correlates of the same CCA. Based on the available evidence, we hypothesized that diverse CCAs are all positively but only weakly associated with rGMV in widespread brain areas. To test this hypothesis, we used the data from a large sample of healthy young adults [776 males and 560 females; mean age: 20.8 years, standard deviation (SD) = 0.8] and investigated associations between rGMV and scores on multiple CCA tasks (including non-verbal reasoning, verbal working memory, Stroop interference, and complex processing speed tasks involving spatial cognition and reasoning). Better performance scores on all tasks except non-verbal reasoning were associated with greater rGMV across widespread brain areas. The effect sizes of individual associations were generally low, consistent with our previous studies. The lack of strong correlations between rGMV and specific CCAs, combined with stringent corrections for multiple comparisons, may lead to different and diverse findings in the field.
Attentional Control in Adolescent Mice Assessed with a Modified Five Choice Serial Reaction Time Task
Authors: Ciampoli Mariasole , Contarini Gabriella , Mereu Maddalena , Papaleo Francesco
Published: August 2017

Adolescence is a critical period for the development of higher-order cognitive functions. Unlike in humans, very limited tools are available to assess such cognitive abilities in adolescent rodents. We implemented a modified 5-Choice Serial Reaction Time Task (5CSRTT) to selectively measure attentiveness, impulsivity, broad monitoring, processing speed and distractibility in adolescent mice. 21-day old C57BL/6J mice reliably acquired this task with no sex-dependent differences in 10–12 days. A protocol previously used in adults was less effective to assess impulsiveness in adolescents, but revealed increased vulnerability in females. Next, we distinctively assessed selective, divided and broad monitoring attention modeling the human Spatial Attentional Resource Allocation Task (SARAT). Finally, we measured susceptibility to distractions using non-predictive cues that selectively disrupted attention. These paradigms were also applied to two genetically modified lines: the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT) heterozygous. Adolescent DAT hypo-functioning mice showed attentional deficits and higher impulsivity as found in adults. In contrast to adults, adolescent COMT hypo-functioning mice showed decreased impulsivity and attentional resilience to distractors. These paradigms open new avenues to study the establishment of higher-order cognitive functions in mice, as well as an effective tool for drug-testing and genetic screenings focused on adolescence.
On the determination of the temperature distribution within the color conversion elements of phosphor converted LEDs
Authors: Nemitz Wolfgang , Fulmek Paul , Nicolics Johann , Reil Frank , Wenzl Franz P.
Published: August 2017

We present an iterative optical and thermal simulation procedure which enables the determination of the temperature distribution in the phosphor layer of a phosphor converted LED with good accuracy. Using the simulation both the highest phosphor temperatures, which are mostly relevant to material degradation as well as the temperatures of those phosphor particles which mainly contribute to converted light emission can be determined. We compare the simulations with experimental studies on the phosphor temperature. While infrared thermography only gives information on the phosphor layer surface temperature, phosphor thermometry provides temperature data on the volume temperature of the phosphor layer relevant to color conversion.
Mastering the Wrinkling of Self-supported Graphene
Authors: Pacakova Barbara , Verhagen Tim , Bousa Milan , Hübner Uwe , Vejpravova Jana , Kalbac Martin , Frank Otakar
Published: August 2017

We present an approach that allows for the preparation of well-defined large arrays of graphene wrinkles with predictable geometry. Chemical vapor deposition grown graphene transferred onto hexagonal pillar arrays of SiO2 with sufficiently small interpillar distance forms a complex network of two main types of wrinkle arrangements. The first type is composed of arrays of aligned equidistantly separated parallel wrinkles propagating over large distances, and originates from line interfaces in the graphene, such as thin, long wrinkles and graphene grain boundaries. The second type of wrinkle arrangement is composed of non-aligned short wrinkles, formed in areas without line interfaces. Besides the presented hybrid graphene topography with distinct wrinkle geometries induced by the pre-patterned substrate, the graphene layers are suspended and self-supporting, exhibiting large surface area and negligible doping effects from the substrate. All these properties make this wrinkled graphene a promising candidate for a material with enhanced chemical reactivity useful in nanoelectronic applications.
Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors
Authors: Chakraborty Srirupa , Das Payel
Published: August 2017

Alzheimer’s disease (AD) is characterized by deposition of amyloid beta (Aβ) peptides into senile plaques in the brain. While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human Aβ variants,i.e. A2T and A2V, in the heterozygous state. The mixture of A2V Aβ1-6 (Aβ6) hexapeptide and WT Aβ1–42 (Αβ42) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T Aβ6hexapeptide binding on the monomeric WT Aβ42landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of Aβ42with the A2V and A2T hexapeptides compared to WT Aβ6. A notable reorganization of the Aβ42landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, Aβ6-bound Aβ42monomer exhibits alternative structural features that are strongly dependent on the hexapeptide sequence. For example, a central helix is more frequently populated within the A2T-bound monomer, while A2V-bound Aβ42is often enhanced in overall disorder. Taken together, the present simulations offer novel molecular insights onto the effect of the N-terminal hexapeptide binding on the Aβ42monomer structure, which might help in explaining their reported amyloid inhibition properties.
α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication
Authors: Aulić Suzana , Masperone Lara , Narkiewicz Joanna , Isopi Elisa , Bistaffa Edoardo , Ambrosetti Elena , Pastore Beatrice , De Cecco Elena , Scaini Denis , Zago Paola , Moda Fabio , Tagliavini Fabrizio , Legname Giuseppe
Published: August 2017

The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrPC) in mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that the presence of PrPC fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed in vivo in wild type (Prnp+/+) compared to PrP knock-out (Prnp−/−) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrPSc) in vitro and ex vivo, indicating a link between the two proteins. Indeed, whilst PrPC is mediating the internalization of α-Syn amyloids, PrPSc is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course.
Electronic Metamaterials with Tunable Second-order Optical Nonlinearities
Authors: Lin Hung-Hsi , Vallini Felipe , Yang Mu-Han , Sharma Rajat , Puckett Matthew W. , Montoya Sergio , Wurm Christian D. , Fullerton Eric E. , Fainman Yeshaiahu
Published: August 2017

The ability to engineer metamaterials with tunable nonlinear optical properties is crucial for nonlinear optics. Traditionally, metals have been employed to enhance nonlinear optical interactions through field localization. Here, inspired by the electronic properties of materials, we introduce and demonstrate experimentally an asymmetric metal-semiconductor-metal (MSM) metamaterial that exhibits a large and electronically tunable effective second-order optical susceptibility (χ(2)). The induced χ(2) originates from the interaction between the third-order optical susceptibility of the semiconductor (χ(3)) with the engineered internal electric field resulting from the two metals possessing dissimilar work function at its interfaces. We demonstrate a five times larger second-harmonic intensity from the MSM metamaterial, compared to contributions from its constituents with electrically tunable nonlinear coefficient ranging from 2.8 to 15.6 pm/V. Spatial patterning of one of the metals on the semiconductor demonstrates tunable nonlinear diffraction, paving the way for all-optical spatial signal processing with space-invariant and -variant nonlinear impulse response.
Co-encapsulation and co-transplantation of mesenchymal stem cells reduces pericapsular fibrosis and improves encapsulated islet survival and function when allografted
Authors: Vaithilingam Vijayaganapathy , Evans Margaret D. M. , Lewy Denise M. , Bean Penelope A. , Bal Sumeet , Tuch Bernard E.
Published: August 2017

Pericapsular fibrotic overgrowth (PFO) is associated with poor survival of encapsulated islets. A strategy to combat PFO is the use of mesenchymal stem cells (MSC). MSC have anti-inflammatory properties and their potential can be enhanced by stimulation with proinflammatory cytokines. This study investigated whether co-encapsulation or co-transplantation of MSC with encapsulated islets would reduce PFO and improve graft survival. Stimulating MSC with a cytokine cocktail of IFN-γ and TNF-α enhanced their immunosuppressive potential by increasing nitric oxide production and secreting higher levels of immunomodulatory cytokines. In vitro, co-encapsulation with MSC did not affect islet viability but significantly enhanced glucose-induced insulin secretion. In vivo, normoglycemia was achieved in 100% mice receiving islets co-encapsulated with stimulated MSC as opposed to 71.4% receiving unstimulated MSC and only 9.1% receiving encapsulated islets alone. Microcapsules retrieved from both unstimulated and stimulated MSC groups had significantly less PFO with improved islet viability and function compared to encapsulated islets alone. Levels of peritoneal immunomodulatory cytokines IL-4, IL-6, IL-10 and G-CSF were significantly higher in MSC co-encapsulated groups. Similar results were obtained when encapsulated islets and MSC were co-transplanted. In summary, co-encapsulation or co-transplantation of MSC with encapsulated islets reduced PFO and improved the functional outcome of allotransplants.
Hydrological legacy determines the type of enzyme inhibition in a peatlands chronosequence
Authors: Bonnett Samuel Alexander Festing , Maltby Edward , Freeman Chris
Published: August 2017

Peatland ecosystems contain one-third of the world’s soil carbon store and many have been exposed to drought leading to a loss of carbon. Understanding biogeochemical mechanisms affecting decomposition in peatlands is essential for improving resilience of ecosystem function to predicted climate change. We investigated biogeochemical changes along a chronosequence of hydrological restoration (dry eroded gully, drain-blocked <2 years, drain blocked <7 years and wet pristine site), and examined whether hydrological legacy alters the response of β-glucosidase kinetics (i.e. type of inhibition) to short-term drying and waterlogging. In the dry eroded gully at depth, low phenolic concentrations were associated with enhanced β-glucosidase enzyme activities (V
max
) but short-term drying and waterlogging caused a significant increase of dissolved organic carbon (DOC) and phenolics associated with increases in V
max
(enzyme production) and K
m
(indicative of competitive inhibition). Inhibition within the drain blocked and pristine sites at depth exhibited non-competitive inhibition (decreased Vmax), whilst uncompetitive inhibition (decreased V
max
and K
m
) occurred in surface peat explained by variation in humic substances and phenolics. These results suggest that loss of carbon by short-term drought or rewetting may occur from sites with a legacy of drought due to the release of non-inhibitory phenolics that permits enhanced enzyme activity.
Immune activated monocyte exosomes alter microRNAs in brain endothelial cells and initiate an inflammatory response through the TLR4/MyD88 pathway
Authors: Dalvi Pranjali , Sun Bing , Tang Norina , Pulliam Lynn
Published: August 2017

The host immune response is critical for homeostasis; however, when chronic low level activation of the immune response with or without the driver continues, a cascade of events can trigger immunological dysfunction. Monocytes are key peripheral sensors of the immune response and their activation is instrumental in the development of cognitive impairment. Here, we show that monocytes activated by interferon alpha, lipopolysaccharide or a combination of both generate exosomes carrying significantly altered microRNA profiles compared to non-activated monocytes. These exosomes alone can activate human brain microvascular endothelial cells to stimulate adhesion molecules, CCL2, ICAM1, VCAM1 and cytokines, IL1β and IL6. This activation is through the toll like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) pathway that activates nuclear factor-κB and increases monocyte chemotaxis. Inhibition of monocyte exosome release reverses endothelial cell activation and monocyte chemotaxis. Our study suggests that activated monocytes have an impact on brain vascular function through intercellular exosome signaling.
Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS
Authors: D’Erchia Anna Maria , Gallo Angela , Manzari Caterina , Raho Susanna , Horner David S. , Chiara Matteo , Valletti Alessio , Aiello Italia , Mastropasqua Francesca , Ciaccia Loredana , Locatelli Franco , Pisani Francesco , Nicchia Grazia Paola , Svelto Maria , Pesole Graziano , Picardi Ernesto
Published: August 2017

ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Although much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. In the present work, we have deeply sequenced whole transcriptome from spinal cord ventral horns of post-mortem ALS human donors affected by the sporadic form of the disease (which comprises ~90% of the cases but which is less investigated than the inherited form of the disease). We observe 1160 deregulated genes including 18 miRNAs and show that down regulated genes are mainly of neuronal derivation while up regulated genes have glial origin and tend to be involved in neuroinflammation or cell death. Remarkably, we find strong deregulation of SNAP25 and STX1B at both mRNA and protein levels suggesting impaired synaptic function through SNAP25 reduction as a possible cause of calcium elevation and glutamate excitotoxicity. We also note aberrant alternative splicing but not disrupted RNA editing.
Functional proteomics outlines the complexity of breast cancer molecular subtypes
Authors: Gámez-Pozo Angelo , Trilla-Fuertes Lucía , Berges-Soria Julia , Selevsek Nathalie , López-Vacas Rocío , Díaz-Almirón Mariana , Nanni Paolo , Arevalillo Jorge M. , Navarro Hilario , Grossmann Jonas , Gayá Moreno Francisco , Gómez Rioja Rubén , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Main Paloma , Feliú Jaime , Martínez del Prado Purificación , Zamora Pilar , Ciruelos Eva , Espinosa Enrique , Fresno Vara Juan Ángel
Published: August 2017

Breast cancer is a heterogeneous disease comprising a variety of entities with various genetic backgrounds. Estrogen receptor-positive, human epidermal growth factor receptor 2-negative tumors typically have a favorable outcome; however, some patients eventually relapse, which suggests some heterogeneity within this category. In the present study, we used proteomics and miRNA profiling techniques to characterize a set of 102 either estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) or triple-negative formalin-fixed, paraffin-embedded breast tumors. Protein expression-based probabilistic graphical models and flux balance analyses revealed that some ER+/PR+ samples had a protein expression profile similar to that of triple-negative samples and had a clinical outcome similar to those with triple-negative disease. This probabilistic graphical model-based classification had prognostic value in patients with luminal A breast cancer. This prognostic information was independent of that provided by standard genomic tests for breast cancer, such as MammaPrint, OncoType Dx and the 8-gene Score.
PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting
Authors: Lee Jae-Ho , Kang Hye Suk , Park Hyeon Young , Moon Young-Ah , Kang Yu Na , Oh Byung-Chul , Song Dae-Kyu , Bae Jae-Hoon , Im Seung-Soon
Published: August 2017

Peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed. In the present study, we found that Insig2a was upregulated by PPARα in mouse livers and primary hepatocytes during fasting, whereas Insig2a mRNA expression was decreased in the livers of refed mice. A PPAR-responsive element between −126 bp and −114 bp in the Insig2a promoter was identified by a transient transfection assay and a chromatin immunoprecipitation assay; its role in regulation by PPARα was characterised using Pparα-null mice. These results suggest that PPARα is a trans-acting factor that enhances Insig2a gene expression, thereby suppressing SREBP-1c processing during fasting.
PPARα activation protects against cholestatic liver injury
Authors: Zhao Qi , Yang Rui , Wang Jing , Hu Dan-Dan , Li Fei
Published: August 2017

Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which ultimately may lead to liver fibrosis and cirrhosis. Here, the preventive and therapeutic effects of peroxisome proliferator-activated receptor α (PPARα) signaling activated by fenofibrate was evaluated on cholestatic liver damage. Metabolomic analysis revealed that alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis resulted in the accumulation of serum long-chain acylcarnitines and triglyceride, and the reduced expression of four fatty acid β-oxidation (β-FAO) relevant genes (Cpt1b, Cpt2, Mcad and Hadha), indicating the disruption of β-FAO. The increase of acylcarnitines in hepatic cell resulted in the enhanced expression of anti-oxidative genes glutathione S-transferases (Gsta2 and Gstm3) directly. As direct PPARα-regulated genes, Cpt1b, Cpt2, and Mcad were up-regulated after pretreatment with PPARα agonist, fenofibrate, indicating the improvement of β-FAO. In the end, the disrupted bile acid metabolism in the enterohepatic circulation and the enhanced oxidative stress and inflammation cytokines induced by ANIT exposure were significantly recovered with the improvement of β-FAO using fenofibrate treatment. These findings provide the rationale for the use of PPARα agonists as therapeutic alternatives for cholestatic liver damage.
The molecular basis of differential morphology and bleaching thresholds in two morphs of the coral Pocillopora acuta
Authors: Smith Hillary , Epstein Hannah , Torda Gergely
Published: August 2017

Processes of cnidarian evolution, including hybridization and phenotypic plasticity, have complicated the clear diagnosis of species boundaries within the phylum. Pocillopora acuta, a species of scleractinian coral that was recently split from the widespread Pocillopora damicornis species complex, occurs in at least two distinct morphs on the Great Barrier Reef. Contrasting morphology combined with evidence of differential bleaching thresholds among sympatrically distributed colonies suggest that the taxonomy of this recently described species is not fully resolved and may represent its own species complex. To examine the basis of sympatric differentiation between the two morphs, we combined analyses of micro- and macro-skeletal morphology with genome wide sequencing of the coral host, as well as ITS2 genotyping of the associated Symbiodinium communities. We found consistent differences between morphs on both the macro- and micro-skeletal scale. In addition, we identified 18 candidate functional genes that relate to skeletal formation and morphology that may explain how the two morphs regulate growth to achieve their distinct growth forms. With inconclusive results in endosymbiotic algal community diversity between the two morphs, we propose that colony morphology may be linked to bleaching susceptibility. We conclude that cryptic speciation may be in the early stages within the species P. acuta.
Detection of frequency-dependent endothelial response to oscillatory shear stress using a microfluidic transcellular monitor
Authors: Sei Yoshitaka J. , Ahn Song Ih , Virtue Theodore , Kim Taeyoung , Kim YongTae
Published: August 2017

The endothelial microenvironment is critical in maintaining the health and function of the intimal layer in vasculature. In the context of cardiovascular disease (CVD), the vascular endothelium is the layer of initiation for the progression of atherosclerosis. While laminar blood flows are known to maintain endothelial homeostasis, disturbed flow conditions including those the endothelium experiences in the carotid artery are responsible for determining the fate of CVD progression. We present a microfluidic device designed to monitor the endothelium on two fronts: the real-time monitoring of the endothelial permeability using integrated electrodes and the end-point characterization of the endothelium through immunostaining. Our key findings demonstrate endothelial monolayer permeability and adhesion protein expression change in response to oscillatory shear stress frequency. These changes were found to be significant at certain frequencies, suggesting that a frequency threshold is needed to elicit an endothelial response. Our device made possible the real-time monitoring of changes in the endothelial monolayer and its end-point inspection through a design previously absent from the literature. This system may serve as a reliable research platform to investigate the mechanisms of various inflammatory complications of endothelial disorders and screen their possible therapeutics in a mechanistic and high-throughput manner.
Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer
Authors: Nieskoski Michael D. , Marra Kayla , Gunn Jason R. , Hoopes P. Jack , Doyley Marvin M. , Hasan Tayyaba , Trembly B. Stuart , Pogue Brian W.
Published: August 2017

The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro﻿-regional﻿ interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics.
Role of 2D and 3D defects on the reduction of LaNiO3 nanoparticles for catalysis
Authors: Singh Sarika , Prestat Eric , Huang Liang-Feng , Rondinelli James M. , Haigh Sarah J. , Rosen Brian A.
Published: August 2017

Solid phase crystallization offers an attractive route to synthesize Ni nanoparticles on a La2O3 support. These materials have shown great promise as catalysts for methane oxidation and similar reactions. Synthesis is achieved by the reduction of a LaNiO3 (LNO) precursor at high temperatures, but the reduction pathway can follow a variety of routes. Optimization of catalytic properties such as the long-term stability has been held back by a lack of understanding of the factors impacting the reduction pathway, and its strong influence on the structure of the resulting Ni/La2O3 catalyst. Here we show the first evidence of the importance of extended structural defects in the LNO precursor material (2D stacking faults and 3D inclusions) for determining the reaction pathway and therefore the properties of the final catalyst. Here we compare the crystallization of LNO nanoparticles via two different pathways using in-situ STEM, in-situ synchrotron XRD, and DFT electronic structure calculations. Control of extended defects is shown to be a key microstructure component for improving catalyst lifetimes.