bluuebunny/crossref_metadata_2025 huggingface dataset:
Abundance of manatees in Panama estimated from side‐scan sonar
Authors: Guzman Hector M. , Condit Richard
Published: August 2017

The Antillean manatee (Trichechus manatus manatus) is found in tropical and subtropical riverine and coastal waters across the Caribbean region. Little is known of its population status, particularly in Central America. We counted and mapped manatees using side‐scan sonar in the San San Pond Sak wetland, a protected estuary in western Panama, for 12 months, and converted the sightings into density and abundance estimates. A total of 214 sonar transects, covering 1,731 km and detecting 1,004 manatees, were completed. The greatest density of animals was found in the narrow and relatively deep upstream tributaries and also in a shallow lagoon near the river mouth. The estimated mean number of manatees in the 18‐km San San River system over the year was 18.3, but abundance was highly seasonal, with 33 animals present in May and just 2 animals in December. These figures are within the range reported for similar rivers in Central America and Florida, USA. Uncertainty of the population size was estimated with a Bayesian model, using daily variance in counts, and 95% credible intervals were 22–71 animals at peak season but just 1–6 animals in December. The active sonar survey used in this study located manatees, mapped their positions, and converted sightings into quantitative data for rigorous analysis. The method is cost‐effective for repeated counts across seasons and years, needed to evaluate population trends. © 2017 The Wildlife Society.
The Phospholipid Composition of Kangaroo Spermatozoa Verified by Mass Spectrometric Lipid Analysis
Authors: Engel Kathrin M. , Schiller Jürgen , Müller Karin , Dannenberger Dirk , Jakop Ulrike
Published: August 2017

Cryopreservation of kangaroo sperm has not been successful so far, and yet there is no promising cryopreservation protocol for these cells available. However, conservation of gametes is extremely important, particularly in the context of preserving endangered species. As spermatozoa are comprised of different membrane systems, the composition of these membranes might account for difficulties in cryopreservation. Lipids, as the main components, affect the physical properties of biological membranes and play a major role in sperm maturation. Therefore, knowledge of the lipid composition is crucial for any further step toward the preservation of the species. We used MALDI‐TOF, ESI‐IT, tandem mass spectrometry, and thin layer chromatography to investigate the lipid composition of epididymal spermatozoa of four different kangaroo species. Spectra of these species were very similar with respect to the identified lipid species. Tremendous changes in the lipid composition during the transit of sperm from caput to cauda epididymis could be seen, specifically an increase in poly‐unsaturated fatty acids, ether lipids, and plasmalogens, as well as a reduction in mono‐ and di‐unsaturated fatty acids. Additionally, phosphatidylcholines containing docosatrienoic acid (22:3), a heretofore unknown fatty acid for sperm membranes, showed the highest abundance in kangaroo sperm.
Dispute Settlement Reports 2014
Authors: World Trade Organization
Published: August 2017

The Dispute Settlement Reports of the World Trade Organization (WTO) include Panel and Appellate Body reports, as well as arbitration awards, in disputes concerning the rights and obligations of WTO members under the provisions of the Marrakesh Agreement Establishing the World Trade Organization. These are the WTO authorized and paginated reports in English. An essential addition to the library of all practicing and academic trade lawyers and needed by students worldwide taking courses in international economic or trade law. DSR 2014: Volume 5 reports on United States - Countervailing Measures on Certain Hot-Rolled Carbon Steel Flat Products from India (WT/DS436).
Dispute Settlement Reports 2014
Authors: World Trade Organization
Published: August 2017

The Dispute Settlement Reports of the World Trade Organization (WTO) include Panel and Appellate Body reports, as well as arbitration awards, in disputes concerning the rights and obligations of WTO members under the provisions of the Marrakesh Agreement Establishing the World Trade Organization. These are the WTO authorized and paginated reports in English. An essential addition to the library of all practicing and academic trade lawyers and needed by students worldwide taking courses in international economic or trade law. DSR 2014: Volume 1 reports on European Communities - Measures Prohibiting the Importation and Marketing of Seal Products (WT/DS400, WT/DS401).
Dispute Settlement Reports 2015
Authors: World Trade Organization
Published: August 2017

The Dispute Settlement Reports of the World Trade Organization (WTO) include Panel and Appellate Body reports, as well as arbitration awards, in disputes concerning the rights and obligations of WTO members under the provisions of the Marrakesh Agreement Establishing the World Trade Organization. These are the WTO authorized and paginated reports in English. An essential addition to the library of all practicing and academic trade lawyers and needed by students worldwide taking courses in international economic or trade law. DSR 2015: Volume 2 reports on Argentina - Measures Affecting the Importation of Goods (WT/DS438, WT/DS444, WT/DS445).
Dispute Settlement Reports 2015
Authors: World Trade Organization
Published: August 2017

The Dispute Settlement Reports of the World Trade Organization (WTO) include Panel and Appellate Body reports, as well as arbitration awards, in disputes concerning the rights and obligations of WTO members under the provisions of the Marrakesh Agreement Establishing the World Trade Organization. These are the WTO authorized and paginated reports in English. An essential addition to the library of all practicing and academic trade lawyers and needed by students worldwide taking courses in international economic or trade law. DSR 2015: Volume 3 reports on United States - Anti-Dumping Measures on Certain Shrimp from Viet Nam (WT/DS429).
Meal-specific food patterns and the incidence of hyperglycemia in a Chinese adult population
Authors: Shi Zumin , Riley Malcolm , Taylor Anne , Noakes Manny
Published: August 2017

This study aimed to examine the association between meal-specific food patterns and incident hyperglycaemia in a Chinese adult population. Adults aged 20 years and older (n 1056) were followed from 2002 to 2007. Dietary data were collected using a 3-d food record and meal-specific (breakfast, lunch and dinner) food patterns were independently described by factor analysis based on the consumption of thirty-five food groups at each eating occasion. Each food pattern score was recoded as quartiles. Hyperglycaemia was defined as fasting plasma glucose >5·6 mmol/l at baseline and follow-up. The associated between food patterns and incident hyperglycaemia was assessed by logistic regression. During the follow-up, 125 new cases of hyperglycaemia were identified. Traditional (wheat) breakfast was inversely associated with incident hyperglycaemia, whereas traditional (rice, vegetable and pork) lunch and dinner were positively associated with the risk of incident hyperglycaemia, even after adjustment for a number of covariates including glycaemic load, carbohydrate intake and BMI. Incident hyperglycaemia occurred in 15·9, 13·6, 11·7, 6·1 % across quartiles of traditional breakfast; and 5·3, 9·1, 15·9, 17·1 % of the quartiles of traditional lunch pattern. The adjusted OR for hyperglycaemia was 0·67 (95 % CI 0·48, 0·92), 1·83 (95 % CI 1·32, 2·53) and 1·39 (95 % CI 1·04, 1·86) for 1 sd increase of traditional breakfast, lunch and dinner pattern factor score, respectively. A traditional wheat-based breakfast is associated with a decreased risk of hyperglycaemia. A rice-based traditional lunch and dinner is associated with an increased risk of hyperglycaemia in Chinese adults.
The role of elite rivalry and ethnic politics in livestock raids in northern Kenya
Authors: Okumu Willis , Bukari Kaderi Noagah , Sow Papa , Onyiego Evans
Published: August 2017

This paper argues that livestock raids and pastoralists’ competition over water and pastures in north-western Kenya are manifestations of local ethnic political contests and rivalries. The culture of raiding among the Samburu, Turkana, Pokot, Borana, Gabra and Rendille communities has changed over the last 40 years. Whereas elders were once the gatekeepers of communal institutions, today new actors are at the forefront of new forms of violent raids. Among Samburu and Turkana communities, politicians and shrewd businessmen have emerged to exploit ethnic rivalry that exists between these groups and use it to mobilise raids. These political and business elites play influencing roles in raiding by paying and arming warriors to carry out raids. Competition for political influence is closely intertwined with competition over scarce water resources and grazing pastures among Turkana and Samburu. Given that pastoralists survive on decreasing pasture and water resources, our study shows that political elites arm their communities during the dry season to gain the upper hand in contests over access to limited resources. Livestock raids no longer occur in the traditional context of restocking, but rather as an expression and manifestation of local ethnic politics and political contests between ethnic kingpins. The study uses primary field data from a case study collected through in-depth interviews, oral history and group discussions with various actors.
Land conflicts and social differentiation in eastern Uganda
Authors: Kandel Matt
Published: August 2017

Rising competition and conflict over land in rural sub-Saharan Africa continues to attract the attention of researchers. Recent work has especially focused on land governance, post-conflict restructuring of tenure relations, and large-scale land acquisitions. A less researched topic as of late, though one deserving of greater consideration, pertains to how social differentiation on the local-level shapes relations to land, and how these processes are rooted in specific historical developments. Drawing on fieldwork conducted in Teso sub-region of eastern Uganda, this paper analyses three specific land conflicts and situates them within a broad historical trajectory. I show how each dispute illuminates changes in class relations in Teso since the early 1990s. I argue that this current period of socioeconomic transformation, which includes the formation of a more clearly defined sub-regional middle class and elite, constitutes the most prominent period of social differentiation in Teso since the early 20th century.
Unconscious Pleasures and Attitudinal Theories of Pleasure
Authors: HEATHWOOD CHRIS
Published: August 2017

This article responds to a new objection, due to Ben Bramble, against attitudinal theories of sensory pleasure and pain: the objection from unconscious pleasures and pains. According to the objection, attitudinal theories are unable to accommodate the fact that sometimes we experience pleasures and pains of which we are, at the time, unaware. In response, I distinguish two kinds of unawareness and argue that the subjects in the examples that support the objection are unaware of their sensations in only a weak sense, and this weak sort of unawareness of a sensation does not preclude its being an object of one's attitudes.
SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway
Authors: Xie Ning , Chen Min , Dai Rilei , Zhang Yan , Zhao Hanqing , Song Zhiming , Zhang Lufeng , Li Zhenyan , Feng Yuanqing , Gao Hua , Wang Li , Zhang Ting , Xiao Rui-Ping , Wu Jianxin , Cao Chun-Mei
Published: August 2017

Though vascular smooth muscle cell (VSMC) proliferation underlies all cardiovascular hyperplastic disorders, our understanding of the molecular mechanisms responsible for this cellular process is still incomplete. Here we report that SRSF1 (serine/arginine-rich splicing factor 1), an essential splicing factor, promotes VSMC proliferation and injury-induced neointima formation. Vascular injury in vivo and proliferative stimuli in vitro stimulate SRSF1 expression. Mice lacking SRSF1 specifically in SMCs develop less intimal thickening after wire injury. Expression of SRSF1 in rat arteries enhances neointima formation. SRSF1 overexpression increases, while SRSF1 knockdown suppresses the proliferation and migration of cultured human aortic and coronary arterial SMCs. Mechanistically, SRSF1 favours the induction of a truncated p53 isoform, Δ133p53, which has an equal proliferative effect and in turn transcriptionally activates Krüppel-like factor 5 (KLF5) via the Δ133p53-EGR1 complex, resulting in an accelerated cell-cycle progression and increased VSMC proliferation. Our study provides a potential therapeutic target for vascular hyperplastic disease.
Agricultural pesticide use and adverse birth outcomes in the San Joaquin Valley of California
Authors: Larsen Ashley E. , Gaines Steven D. , Deschênes Olivier
Published: August 2017

Virtually all agricultural communities worldwide are exposed to agricultural pesticides. Yet, the health consequences of such exposure are poorly understood, and the scientific literature remains ambiguous. Using individual birth and demographic characteristics for over 500 000 birth observations between 1997–2011 in the agriculturally dominated San Joaquin Valley, California, we statistically investigate if residential agricultural pesticide exposure during gestation, by trimester, and by toxicity influences birth weight, gestational length, or birth abnormalities. Overall, our analysis indicates that agricultural pesticide exposure increases adverse birth outcomes by 5–9%, but only among the population exposed to very high quantities of pesticides (e.g., top 5th percentile, i.e., ~4200 kg applied over gestation). Thus, policies and interventions targeting the extreme right tail of the pesticide distribution near human habitation could largely eliminate the adverse birth outcomes associated with agricultural pesticide exposure documented in this study.
Platelets reduce anoikis and promote metastasis by activating YAP1 signaling
Authors: Haemmerle Monika , Taylor Morgan L. , Gutschner Tony , Pradeep Sunila , Cho Min Soon , Sheng Jianting , Lyons Yasmin M. , Nagaraja Archana S. , Dood Robert L. , Wen Yunfei , Mangala Lingegowda S. , Hansen Jean M. , Rupaimoole Rajesha , Gharpure Kshipra M. , Rodriguez-Aguayo Cristian , Yim Sun Young , Lee Ju-Seog , Ivan Cristina , Hu Wei , Lopez-Berestein Gabriel , Wong Stephen T. , Karlan Beth Y. , Levine Douglas A. , Liu Jinsong , Afshar-Kharghan Vahid , Sood Anil K.
Published: August 2017

Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process.
Anti-biofilm effects of anthranilate on a broad range of bacteria
Authors: Li Xi-Hui , Kim Soo-Kyoung , Lee Joon-Hee
Published: August 2017

Anthranilate, one of tryptophan degradation products has been reported to interfere with biofilm formation by Pseudomonas aeruginosa. Here, we investigated the effects of anthranilate on biofilm formation by various bacteria and the mechanisms responsible. Anthranilate commonly inhibited biofilm formation by P. aeruginosa, Vibrio vulnificus, Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus, and disrupted biofilms preformed by these bacteria. Because anthranilate reduced intracellular c-di-GMP and enhanced swimming and swarming motilities in P. aeruginosa, V. vulnificus, B. subtilis, and S. enterica, it is likely that anthranilate disrupts biofilms by inducing the dispersion of these bacteria. On the other hand, in S. aureus, a non-flagellate bacterium that has no c-di-GMP signaling, anthranilate probably inhibits biofilm formation by reducing slime production. These results suggest that anthranilate has multiple ways for biofilm inhibition. Furthermore, because of its good biofilm inhibitory effects and lack of cytotoxicity to human cells even at high concentration, anthranilate appears to be a promising agent for inhibiting biofilm formation by a broad range of bacteria.
Thyroid function and ischemic heart disease: a Mendelian randomization study
Authors: Zhao Jie V. , Schooling C. Mary
Published: August 2017

To clarify the role of thyroid function in ischemic heart disease (IHD) we assessed IHD risk and risk factors according to genetically predicted thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) positivity. Separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) was used in an extensively genotyped case (n = 64,374)-control (n = 130,681) study, CARDIoGRAMplusC4D. Associations with lipids, diabetes and adiposity were assessed using the Global Lipids Genetics Consortium Results (n = 196,475), the DIAbetes Genetics Replication And Meta-analysis case (n = 34,380)-control (n = 114,981) study, and the Genetic Investigation of ANthropometric Traits (body mass index in 152,893 men and 171,977 women, waist-hip ratio in 93,480 men and 116,741 women). Genetically predicted thyroid function was not associated with IHD (odds ratio (OR) per standard deviation for TSH 1.05, 95% confidence interval (CI) 0.97 to 1.12; for FT4 1.01, 95% CI 0.91 to 1.12; for TPOAb positivity 1.10, 95% CI 0.83 to 1.46) or after Bonferroni correction with risk factors, except for an inverse association of FT4 with low-density lipoprotein-cholesterol. The associations were generally robust to sensitivity analyses using a weighted median method and MR Egger. This novel study provides little indication that TSH, FT4 or TPOAb positivity affects IHD, despite potential effects on its risk factors.
Cytolytic DNA vaccine encoding lytic perforin augments the maturation of- and antigen presentation by- dendritic cells in a time-dependent manner
Authors: Wijesundara Danushka K. , Yu Wenbo , Quah Ben J. C. , Eldi Preethi , Hayball John D. , Diener Kerrilyn R. , Voskoboinik Ilia , Gowans Eric J. , Grubor-Bauk Branka
Published: August 2017

The use of cost-effective vaccines capable of inducing robust CD8+T cell immunity will contribute significantly towards the elimination of persistent viral infections and cancers worldwide. We have previously reported that a cytolytic DNA vaccine encoding an immunogen and a truncated mouse perforin (PRF) protein significantly augments anti-viral T cell (including CD8+T cell) immunity. Thus, the current study investigated whether this vaccine enhances activation of dendritic cells (DCs) resulting in greater priming of CD8+T cell immunity.In vitrodata showed that transfection of HEK293T cells with the cytolytic DNA resulted in the release of lactate dehydrogenase, indicative of necrotic/lytic cell death.In vitroexposure of this lytic cell debris to purified DCs from naïve C57BL/6 mice resulted in maturation of DCs as determined by up-regulation of CD80/CD86. Using activation/proliferation of adoptively transferred OT-I CD8+T cells to measure antigen presentation by DCsin vivo, it was determined that cytolytic DNA immunisation resulted in a time-dependent increase in the proliferation of OT-I CD8+T cells compared to canonical DNA immunisation. Overall, the data suggest that the cytolytic DNA vaccine increases the activity of DCs which has important implications for the design of DNA vaccines to improve their translational prospects.
Remote sensing of seasonal light use efficiency in temperate bog ecosystems
Authors: Tortini R. , Coops N. C. , Nesic Z. , Christen A. , Lee S. C. , Hilker T.
Published: August 2017

Despite storing approximately half of the atmosphere’s carbon, estimates of fluxes between wetlands and atmosphere under current and future climates are associated with large uncertainties, and it remains a challenge to determine human impacts on the net greenhouse gas balance of wetlands at the global scale. In this study we demonstrate that the relationship between photochemical reflectance index, derived from high spectral and temporal multi-angular observations, and vegetation light use efficiency was strong (r2 = 0.64 and 0.58 at the hotspot and darkspot, respectively), and can be utilized to estimate carbon fluxes from remote at temperate bog ecosystems. These results improve our understanding of the interactions between vegetation physiology and spectral characteristics to understand seasonal magnitudes and variations in light use efficiency, opening new perspectives on the potential of this technique over extensive areas with different landcover.
Hypotension in ICU Patients Receiving Vasopressor Therapy
Authors: Yapps Bryce , Shin Sungtae , Bighamian Ramin , Thorsen Jill , Arsenault Colleen , Quraishi Sadeq A. , Hahn Jin-Oh , Reisner Andrew T.
Published: August 2017

Vasopressor infusion (VPI) is used to treat hypotension in an ICU. We studied compliance with blood pressure (BP) goals during VPI and whether a statistical model might be efficacious for advance warning of impending hypotension, compared with a basic hypotension threshold alert. Retrospective data were obtained from a public database. Studying adult ICU patients receiving VPI at submaximal dosages, we analyzed characteristics of sustained hypotension episodes (>15 min) and then developed a logistic regression model to predict hypotension episodes using input features related to BP trends. The model was then validated with prospective data. In the retrospective dataset, 102-of-215 ICU stays experienced >1 hypotension episode (median of 2.5 episodes per day in this subgroup). When trained with 75% of retrospective dataset, testing with the remaining 25% of the dataset showed that the model and the threshold alert detected 99.6% and 100% of the episodes, respectively, with median advance forecast times (AFT) of 12 and 0 min. In a second, prospective dataset, the model detected 100% of 26 episodes with a median AFT of 22 min. In conclusion, episodes of hypotension were common during VPI in the ICU. A logistic regression model using BP temporal trend features predicted the episodes before their onset.
Context conditioning in humans using commercially available immersive Virtual Reality
Authors: Kroes Marijn C. W. , Dunsmoor Joseph E. , Mackey Wayne E. , McClay Mason , Phelps Elizabeth A.
Published: August 2017

Despite a wealth of knowledge on how humans and nonhuman animals learn to associate meaningful events with cues in the environment, far less is known about how humans learn to associate these events with the environment itself. Progress on understanding spatiotemporal contextual processes in humans has been slow in large measure by the methodological constraint of generating and manipulating immersive spatial environments in well-controlled laboratory settings. Fortunately, immersive Virtual Reality (iVR) technology has improved appreciably and affords a relatively straightforward methodology to investigate the role of context on learning, memory, and emotion while maintaining experimental control. Here, we review context conditioning literature in humans and describe challenges to study contextual learning in humans. We then provide details for a novel context threat (fear) conditioning paradigm in humans using a commercially available VR headset and a cross-platform game engine. This paradigm resulted in the acquisition of subjective threat, threat-conditioned defensive responses, and explicit threat memory. We make the paradigm publicly available and describe obstacles and solutions to optimize future studies of context conditioning using iVR. As computer technology advances to replicate the sensation of realistic environments, there are increasing opportunities to bridge the translational gap between rodent and human research on how context modulates cognition, which may ultimately lead to more optimal treatment strategies for anxiety- and stress-related disorders.
Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo
Authors: Altenburg Arwen F. , van de Sandt Carolien E. , Li Bobby W. S. , MacLoughlin Ronan J. , Fouchier Ron A. M. , van Amerongen Geert , Volz Asisa , Hendriks Rudi W. , de Swart Rik L. , Sutter Gerd , Rimmelzwaan Guus F. , de Vries Rory D.
Published: August 2017

Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performedin vitro,ex vivoandin vivoexperiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequentin vivoexperiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies.
Long-term (2001–2013) observations of water-soluble dicarboxylic acids and related compounds over the western North Pacific: trends, seasonality and source apportionment
Authors: Boreddy Suresh K. R. , Kawamura Kimitaka , Tachibana Eri
Published: August 2017

To better understand the impact of East Asian pollutants on the molecular composition of marine organic aerosols, we conducted long-term (2001–2013) observations of water-soluble dicarboxylic acids and related compounds in total suspended particulate samples collected at Chichijima Island in the western North Pacific (WNP). Seasonal variations of all the diacids and related compounds showed maxima in winter and spring and minima in summer, except for azelaic acid (C9), which maximized in summer to autumn. The overall annual concentrations of the total diacids, ω-oxoacids and α-dicarbonyls showed an increase during 2001–2013. We found a significant (p < 0.05) decadal increase in the inter-annual trends of pyruvic and glyoxylic (p > 0.05) acids, and methylglyoxal (MeGly). In contrast, phthalic acid (p < 0.05) and glyoxal (Gly) showed a decrease in their trends. We also found a significant decrease in the trend of the Gly/MeGly mass ratios. These results demonstrate that the enhanced concentrations of diacids over the WNP are majorly attributed to the aqueous-phase photooxidation of biogenic volatile organic compounds from East Asia followed by long-range atmospheric transport. Further, positive matrix factorization analysis showed a biogenic photochemical contribution (42%) was the dominant source of oxalic acid in the WNP.
The Gαi-GIV binding interface is a druggable protein-protein interaction
Authors: DiGiacomo Vincent , de Opakua Alain Ibáñez , Papakonstantinou Maria P. , Nguyen Lien T. , Merino Nekane , Blanco-Canosa Juan B. , Blanco Francisco J. , Garcia-Marcos Mikel
Published: August 2017

Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein sequence that directly binds Gαi. GIV expression promotes metastasis and disruption of its binding to Gαi blunts the pro-metastatic behavior of cancer cells. Although this suggests that inhibition of the Gαi-GIV interaction is a promising therapeutic strategy, protein-protein interactions (PPIs) are considered poorly “druggable” targets requiring case-by-case validation. Here, we set out to investigate whether Gαi-GIV is a druggable PPI. We tested a collection of >1,000 compounds on the Gαi-GIV PPI by in silico ligand screening and separately by a chemical high-throughput screening (HTS) assay. Two hits, ATA and NF023, obtained in both screens were confirmed in secondary HTS and low-throughput assays. The binding site of NF023, identified by NMR spectroscopy and biochemical assays, overlaps with the Gαi-GIV interface. Importantly, NF023 did not disrupt Gαi-Gβγ binding, indicating its specificity toward Gαi-GIV. This work establishes the Gαi-GIV PPI as a druggable target and sets the conceptual and technical framework for the discovery of novel inhibitors of this PPI.
Cardiorespiratory pathogenesis of sickle cell disease in a mouse model
Authors: Ren Jun , Ding Xiuqing , Trudel Marie , Greer John J. , MacLean Joanna E.
Published: August 2017

The nature and development of cardiorespiratory impairments associated with sickle cell disease are poorly understood. Given that the mechanisms of these impairments cannot be addressed adequately in clinical studies, we characterized cardiorespiratory pathophysiology from birth to maturity in the sickle cell disease SAD mouse model. We identified two critical phases of respiratory dysfunction in SAD mice; the first prior to weaning and the second in adulthood. At postnatal day 3, 43% of SAD mice showed marked apneas, anemia, and pulmonary vascular congestion typical of acute chest syndrome; none of these mice survived to maturity. The remaining SAD mice had mild lung histological changes in room air with an altered respiratory pattern, seizures, and a high rate of death in response to hypoxia. Approximately half the SAD mice that survived to adulthood had an identifiable respiratory phenotype including baseline tachypnea at 7–8 months of age, restrictive lung disease, pulmonary hypertension, cardiac enlargement, lower total lung capacity, and pulmonary vascular congestion. All adult SAD mice demonstrated impairments in exercise capacity and response to hypoxia, with a more severe phenotype in the tachypneic mice. The model revealed distinguishable subgroups of SAD mice with cardiorespiratory pathophysiology mimicking the complications of human sickle cell disease.
Prognostic factors and outcomes of unplanned extubation
Authors: Chao Chien-Ming , Sung Mei-I. , Cheng Kuo-Chen , Lai Chih-Cheng , Chan Khee-Siang , Cheng Ai-Chin , Hsing Shu-Chen , Chen Chin-Ming
Published: August 2017

This study investigated the prognostic factors and outcomes of unplanned extubation (UE) in patients in a medical center’s 6 intensive care units (ICUs) and calculated their mortality risk. We retrospectively reviewed the medical records of all adult patients in Chi Mei Medical Center who underwent UE between 2009 and 2015. During the study period, there were 305 episodes of UE in 295 ICU patients (men: 199 [67.5%]; mean age: 65.7 years; age range: 18–94 years). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 16.4, mean therapeutic intervention scoring system (TISS) score was 26.5, and mean Glasgow coma scale score was 10.4. One hundred thirty-six patients (46.1%) were re-intubated within 48 h. Forty-five died (mortality rate: 15.3%). Multivariate analyses showed 5 risk factors—respiratory rate, APACHE II score, uremia, liver cirrhosis, and weaning status—were independently associated with mortality. In conclusion, five risk factors including a high respiratory rate before UE, high APACHE II score, uremia, liver cirrhosis, and not in the process of being weaned—were associated with high mortality in patients who underwent UE.
Development and assessment of a lysophospholipid-based deep learning model to discriminate geographical origins of white rice
Authors: Long Nguyen Phuoc , Lim Dong Kyu , Mo Changyeun , Kim Giyoung , Kwon Sung Won
Published: August 2017

Geographical origin determination of white rice has become the major issue of food industry. However, there is still lack of a high-throughput method for rapidly and reproducibly differentiating the geographical origins of commercial white rice. In this study, we developed a method that employed lipidomics and deep learning to discriminate white rice from Korea to China. A total of 126 white rice of 30 cultivars from different regions were utilized for the method development and validation. By using direct infusion-mass spectrometry-based targeted lipidomics, 17 lysoglycerophospholipids were simultaneously characterized within minutes per sample. Unsupervised data exploration showed a noticeable overlap of white rice between two countries. In addition, lysophosphatidylcholines (lysoPCs) were prominent in white rice from Korea while lysophosphatidylethanolamines (lysoPEs) were enriched in white rice from China. A deep learning prediction model was built using 2014 white rice and validated using two different batches of 2015 white rice. The model accurately discriminated white rice from two countries. Among 10 selected predictors, lysoPC(18:2), lysoPC(14:0), and lysoPE(16:0) were the three most important features. Random forest and gradient boosting machine models also worked well in this circumstance. In conclusion, this study provides an architecture for high-throughput classification of white rice from different geographical origins.
Highly Stabilized Core-Satellite Gold Nanoassemblies in Vivo: DNA-Directed Self-Assembly, PEG Modification and Cell Imaging
Authors: Tang Liangfeng , Yu Guiping , Tan Lishan , Li Min , Deng Xiulong , Liu Jianyu , Li Aiqing , Lai Xuandi , Hu Jianqiang
Published: August 2017

Au nanoparticles (NPs) have important applications in bioimaging, clinical diagnosis and even therapy due to its water-solubility, easy modification and drug-loaded capability, however, easy aggregation of Au NPs in normal saline and serum greatly limits its applications. In this work, highly stabilized core-satellite Au nanoassemblies (CSAuNAs) were constructed by a hierarchical DNA-directed self-assembly strategy, in which satellite Au NPs number could be effectively tuned through varying the ratios of core-AuNPs-ssDNA and satellite-AuNPs-ssDNAc. It was especially interesting that PEG-functionalized CSAuNAs (PEG-CSAuNAs) could not only bear saline solution but also resist the enzymatic degradation in fetal calf serum. Moreover, cell targeting and imaging indicated that the PEG-CSAuNAs had promising biotargeting and bioimaging capability. Finally, fluorescence imaging in vivo revealed that PEG-CSAuNAs modified with N-acetylation chitosan (CSNA) could be selectively accumulate in the kidneys with satisfactory renal retention capability. Therefore, the highly stabilized PEG-CSAuNAs open a new avenue for its applications in vivo.
Community outbreaks of group A Streptococcus revealed by genome sequencing
Authors: Turner Claire E. , Bedford Luke , Brown Nicholas M. , Judge Kim , Török M. Estée , Parkhill Julian , Peacock Sharon J.
Published: August 2017

The frequent occurrence of disease outbreaks in humans caused by group A Streptococcus (GAS) is an on-going public health threat. Conventional bacterial typing methods lack the discriminatory power to confidently confirm or refute outbreaks in hospital and community settings. Microbial whole genome sequencing (WGS) provides a potential solution to this, but, there has been limited population-based surveillance with accompanying sequence data. We performed retrospective genomic surveillance of 93 clinical GAS isolates from individuals in a defined geographic region. Detailed clinical information was obtained for closely related clusters of isolates. Genomic sequence data was contextualised through comparison with international data. We identified 18 different emm genotypes within our bacterial population, and revealed both highly diverse and closely related isolates. This high level of diversity was maintained even in the context of international sequence data. We also identified two emm1 clusters, and one emm3 cluster, of closely-related isolates that differed only by 1 to 4 single nucleotide polymorphisms. Analysis of clinical information identified no healthcare associated contact between patients, indicating cryptic community transmission. Our findings suggest that genomic surveillance of GAS would increase detection of transmission and highlight opportunities for intervention.
Curcumin liposomes interfere with quorum sensing system of Aeromonas sobria and in silico analysis
Authors: Ding Ting , Li Tingting , Wang Zhi , Li Jianrong
Published: August 2017

Aeromonas sobria is opportunistic pathogen frequently found in environment and food. Interfering with its quorum sensing (QS) system could be a promising way to alleviate its virulence. In this study, curcumin liposomes were prepared and their characteristics like particle size, zeta potential, PDI (Polymey Disperse Index), encapsulation efficiency and loading capacity were measured. The quorum sensing inhibitory effect of curcumin liposomes under sub-MIC (Minimum Inhibitory Concentration) on siderophore production, swimming and swarming motility, extracellular proteases, biofilm formation and AHLs (N-acylhomoserine lactones) production of A. sobria were also determined. The results showed that, the curcumin liposomes with high encapsulation capacity (84.51 ± 0.58%) were stable and homogeneous. QS-regulated phenotypes of the pathogen were significantly inhibited by curcumin liposomes. The in silico analysis revealed that the QS system of A. sobria may be inhibited by released curcumin from curcumin liposomes through interacting with the built LuxI type protein and blocking the production of AHLs.
The protein and mRNA expression levels of glial cell line-derived neurotrophic factor in post stroke depression and major depressive disorder
Authors: Zhang Yanran , Jiang Haitang , Yue Yingying , Yin Yingying , Zhang Yuqun , Liang Jinfeng , Li Shenghua , Wang Jun , Lu Jianxin , Geng Deqin , Wu Aiqin , Yuan Yonggui
Published: August 2017

Previous studies have indicated that the level of glial cell line-derived neurotrophic factor (GDNF) may be correlated with stroke and depression. Here, we investigated whether GDNF can be a discriminant indicator for post stroke depression (PSD). 159 participants were divided into four groups: PSD, stroke without depression (Non-PSD), major depressive disorder (MDD) and normal control (NC) group, and the protein and mRNA expression levels of GDNF in serum were measured. The results showed that only MDD group had statistical difference in protein and mRNA levels compared with the other three groups (Bonferroni test, P < 0.05). The results of receiver operating curve (ROC) analysis supported GDNF as general distinguishing models in PSD and MDD groups with the area under the curve (AUC) at 0.797 (P < 0.001) and 0.831 (P < 0.001) respectively. In addition, the Spearman analysis demonstrated that the GDNF protein level negatively correlated with the value of Hamilton depression rating scale (HAMD) in PSD patients (correlation coefficient = −0.328,P = 0.047). Together, these findings suggest the protein and mRNA expression levels of GDNF decreased in patients with depression. GDNF may serve as a potential biomarker for differential diagnosis of PSD from MDD patients.
FBN30 in wild Anopheles
gambiae functions as a pathogen recognition molecule against clinically circulating Plasmodium
falciparum in malaria endemic areas in Kenya
Authors: Niu Guodong , Zhang Genwei , Franca Caio , Cui Yingjun , Munga Stephen , Afrane Yaw , Li Jun
Published: August 2017

Malaria is a worldwide health problem that affects two-thirds of the world population. Plasmodium invasion of anopheline mosquitoes is an obligatory step for malaria transmission. However, mosquito-malaria molecular interactions in nature are not clear. A genetic variation within mosquito fibrinogen related-protein 30 (FBN30) was previously identified to be associated with Plasmodium falciparum infection in natural Anopheles gambiae populations at malaria endemic areas in Kenya, and reducing FBN30 expression by RNAi makes mosquitoes more susceptible to P. berghei. New results show that FBN30 is a secreted octamer that binds to both P. berghei and clinically circulating P. falciparum from malaria endemic areas in Kenya, but not laboratory P. falciparum strain NF54. Moreover, the natural genetic mutation (T to C) within FBN30 signal peptide, which changes the position 10 amino acid from phenylalanine to leucine, reduces protein expression by approximately half. This change is consistent to more susceptible An. gambiae to P. falciparum infection in the field. FBN30 in natural An. gambiae is proposed to work as a pathogen recognition molecule in inhibiting P. falciparum transmission in malaria endemic areas.
A multielectrode array microchannel platform reveals both transient and slow changes in axonal conduction velocity
Authors: Habibey Rouhollah , Latifi Shahrzad , Mousavi Hossein , Pesce Mattia , Arab-Tehrany Elmira , Blau Axel
Published: August 2017

Due to their small dimensions, electrophysiology on thin and intricate axonal branches in support of understanding their role in normal and diseased brain function poses experimental challenges. To reduce experimental complexity, we coupled microelectrode arrays (MEAs) to bi-level microchannel devices for the long-term in vitro tracking of axonal morphology and activity with high spatiotemporal resolution. Our model allowed the long-term multisite recording from pure axonal branches in a microscopy-compatible environment. Compartmentalizing the network structure into interconnected subpopulations simplified access to the locations of interest. Electrophysiological data over 95 days in vitro (DIV) showed an age-dependent increase of axonal conduction velocity, which was positively correlated with, but independent of evolving burst activity over time. Conduction velocity remained constant at chemically increased network activity levels. In contrast, low frequency (1 Hz, 180 repetitions) electrical stimulation of axons or network subpopulations evoked amplitude-dependent direct (5–35 ms peri-stimulus) and polysynaptic (35–1,000 ms peri-stimulus) activity with temporarily (<35 ms) elevated propagation velocities along the perisomatic branches. Furthermore, effective stimulation amplitudes were found to be significantly lower (>250 mV) in microchannels when compared with those reported for unconfined cultures (>800 mV). The experimental paradigm may lead to new insights into stimulation-induced axonal plasticity.
Quantifying the free energy landscape between polymers and minerals
Authors: Sand K. K. , Friddle R. W. , DeYoreo J. J.
Published: August 2017

Higher organisms as well as medical and technological materials exploit mineral-polymer interactions, however, mechanistic understanding of these interactions is poorly constrained. Dynamic force spectroscopy can probe the free energy landscape of interacting bonds, but interpretations are challenged by the complex mechanical behavior of polymers. Here we restate the difficulties inherent to applying DFS to polymer-linked adhesion and present an approach to gain quantitative insight into polymer-mineral binding.
Treatment Associated Changes of Functional Connectivity of Midbrain/Brainstem Nuclei in Major Depressive Disorder
Authors: Wagner Gerd , de la Cruz Feliberto , Köhler Stefanie , Bär Karl-Jürgen
Published: August 2017

Previous functional magnetic resonance imaging (fMRI) studies demonstrated an abnormally coordinated network functioning in Major Depression Disorder (MDD) during rest. The main monoamine-producing nuclei within midbrain/brainstem are functionally integrated within these specific networks. Therefore, we aimed to investigate the resting-state functional connectivity (RSFC) of these nuclei in 45 MDD patients and differences between patients receiving two different classes of antidepressant drugs. Patients showed reduced RSFC from the ventral tegmental area (VTA) to dorsal anterior cingulate cortex (dACC) and stronger RSFC to the left amygdala and dorsolateral prefrontal cortex (DLPFC). Patients treated with antidepressants influencing noradrenergic and serotonergic neurotransmission showed different RSFC from locus coeruleus to DLPFC compared to patients treated with antidepressants influencing serotonergic neurotransmission only. In the opposite contrast patients showed stronger RSFC from dorsal raphe to posterior brain regions. Enhanced VTA-RSFC to amygdala as a central region of the salience network may indicate an over‐attribution of the affective salience to internally-oriented processes. Significant correlation between decreased VTA-dACC functional connectivity and the BDI-II somatic symptoms indicates an association with diminished volition and behavioral activation in MDD. The observed differences in the FC of the midbrain/brainstem nuclei between two classes of antidepressants suggest differential neural effects of SSRIs and SNRIs.
Discovering Condition-Specific Gene Co-Expression Patterns Using Gaussian Mixture Models: A Cancer Case Study
Authors: Ficklin Stephen P. , Dunwoodie Leland J. , Poehlman William L. , Watson Christopher , Roche Kimberly E. , Feltus F. Alex
Published: August 2017

A gene co-expression network (GCN) describes associations between genes and points to genetic coordination of biochemical pathways. However, genetic correlations in a GCN are only detectable if they are present in the sampled conditions. With the increasing quantity of gene expression samples available in public repositories, there is greater potential for discovery of genetic correlations from a variety of biologically interesting conditions. However, even if gene correlations are present, their discovery can be masked by noise. Noise is introduced from natural variation (intrinsic and extrinsic), systematic variation (caused by sample measurement protocols and instruments), and algorithmic and statistical variation created by selection of data processing tools. A variety of published studies, approaches and methods attempt to address each of these contributions of variation to reduce noise. Here we describe an approach using Gaussian Mixture Models (GMMs) to address natural extrinsic (condition-specific) variation during network construction from mixed input conditions. To demonstrate utility, we build and analyze a condition-annotated GCN from a compendium of 2,016 mixed gene expression data sets from five tumor subtypes obtained from The Cancer Genome Atlas. Our results show that GMMs help discover tumor subtype specific gene co-expression patterns (modules) that are significantly enriched for clinical attributes.