bluuebunny/crossref_metadata_2025 huggingface dataset:
Up/Rooting: Breaching Landscape Architecture in the Jewish-Arab City
Authors: Meishar Naama
Published: April 2017

This article portrays and theorizes a new utterance of landscape architecture within Israeli Jewish-Arab urbanity, which aims to represent the prolonged and multifaceted Palestinian urban loss since 1948 in the design of a major city park. The analysis of design discourses at Jaffa Slope Park examines differing Israeli and Palestinian landscape sign systems. Dominant and breaching landscape architecture utterances in the constructed landscape of the park will be interpreted and theorized in the context of the discursive landscape sign systems, together with the local post-1948 history of urban institutional ruination and planning. The park's design involves both the intensive use and destabilization of a traditional Zionist/Israeli landscape mold that aims at greening’Ereẓ Yisra'eland at concealing ruined pre-1948 Palestinian locales under green shields. Through a close reading of the park's landscape, the paper explores ethical, political, and allegorical utterances of landscape architecture, immersed in both Israeli and Palestinian landscape semiotics, yet undermining these sign systems at the same time.
Racial inequality in the annual risk of Tuberculosis infection in the United States, 1910–1933
Authors: ZELNER J. L. , MULLER C. , FEIGENBAUM J. J.
Published: April 2017

Tuberculosis (TB) mortality rates in the USA fell rapidly from 1910 to 1933. However, during this period, racial disparities in TB mortality in the nation's expanding cities grew. Because of long delays between infection and disease, TB mortality is a poor indicator of short-term changes in transmission. We estimated the annual risk of TB infection (ARTI) in 11 large US cities to understand whether rising inequality in mortality reflected rising inequality in ARTI using city-level TB mortality data compiled by the US Department of Commerce from 1910 to 1933. We estimated ARTI for African-Americans and whites using pediatric extrapulmonary TB mortality data for African-Americans and whites in our panel of cities. We also estimated age-adjusted pulmonary TB mortality rates for these cities. We find that the ratio of ARTI for African-Americans vs. whites increased from 2·1 (95% CI = 1·7, 2·4) in 1910 to 4·2 (95% CI = 3·4, 5·2) in 1933. This change mirrored the increasing inequality in age-adjusted pulmonary TB mortality during this period. These findings may reflect the combined effects of migration, inequality in access to care, increasing population density, and racial residential segregation in northern cities during this period.
Temperature but not moisture response of germination shows phylogenetic constraints while both interact with seed mass and lifespan
Authors: Arène Fabien , Affre Laurence , Doxa Aggeliki , Saatkamp Arne
Published: April 2017

Understanding how plant traits interact with climate to determine plant niches is decisive for predicting climate change impacts. While lifespan and seed size modify the importance of germination timing, germination traits such as base temperature and base water potential directly translate climatic conditions into germination timing, impacting performance in later life stages. Yet we do not know how base temperature, base water potential, seed mass, lifespan and climate are related. We tested the relationships between base temperature and base water potential for germination, seed size and lifespan while controlling for bioclimatic regions. We also quantified the phylogenetic signal in germination traits and seed size using Pagel's λ. We used a worldwide data set of germination responses to temperature and moisture, seed size and lifespan of 240 seed plants from 49 families. Both germination temperature and moisture are negatively related to seed size. Annual plants show a negative relation between seed size and base water potential, whereas perennials display a negative relation between base temperature and seed mass. Pagel's λ highlighted the slow evolution of base temperature for germination, comparable to seed mass while base water potential was revealed to be labile. In the future, base water potential and seed mass can be used when moisture niches of plants are to be predicted. Lifespan, seed size and base temperature should be taken into account when analysing thermal limits of species distributions.
Reciprocal effect of parental lines on the physiological potential and seed composition of corn hybrid seeds
Authors: Santos Juliana F. , Dirk Lynnette M.A. , Downie A. Bruce , Sanches Mauricio F.G. , Vieira Roberval D.
Published: April 2017

Obtaining corn hybrid seeds (Zea maysL.) with high vigour depends on the parental lines and the direction of the cross, and this relates to seed desiccation tolerance and composition. This research studied reciprocal crosses between pairs of proprietary, elite parent lines (L1 and L5; L2 and L4) producing hybrid seeds with different qualities attempting to correlate vigour with seed composition, focusing on storage proteins, starch and soluble sugar amounts. Four corn hybrid seed lots produced from reciprocal crosses were compared (HS 15 with HS 51, and HS 24 with HS 42) by assessing germination, vigour, and seedling emergence in the field. Seed composition was assessed in mature, dehydrated seeds. Proteins were extracted, quantified, and analysed by electrophoresis and densitometry. Starch amounts were assessed using a kit and soluble sugars were determined using high performance liquid chromatography with pulsed electrochemical detection. The L1 and L2 lineages, used as female parents, provided seeds with lower vigour; however, the quantification of major protein bands, and sucrose, raffinose and stachyose were similar between seed lot pairs. While both total seed protein and starch varied between reciprocal hybrids for one of the two sets of crosses, the amounts of neither correlated with seed vigour. Interestingly, hybrids with low seed vigour (HS 15, HS 24) accumulated greater amounts of fructose relative to their reciprocal; correlation analysis confirmed these results. We demonstrate different effects on seed vigour dependent on the maternal parent in reciprocal crosses producing hybrid corn seeds. We also show that vigour is negatively correlated with seed reducing sugar contents.
TRADE, LUXURY GOODS, AND A GROWTH-ENHANCING TARIFF
Authors: Azarnert Leonid V.
Published: April 2017

This article presents a Ricardian model of trade with learning-by-doing to study the effect of barriers to trade in products with low growth potential on the long-run economic growth. The model shows that, when elasticity of demand for the product with a lower learning potential is greater than unity, a tariff imposed on this product can shift the demand toward the product with a higher learning potential, thus enhancing growth in the exporter economy. Therefore, although with some possible negative effect on the welfare in the short run, barriers for the export of natural luxury goods may be beneficial for developing economies in the long run, since they increase their incentive to develop sectors with higher growth potential.
BEYOND ENDOSCOPY FOR THE RELATIVE TRACE FORMULA II: GLOBAL THEORY
Authors: Sakellaridis Yiannis
Published: April 2017

For the group $G=\operatorname{PGL}_{2}$ we perform a comparison between two relative trace formulas: on the one hand, the relative trace formula of Jacquet for the quotient $T\backslash G/T$, where $T$ is a nontrivial torus, and on the other the Kuznetsov trace formula (involving Whittaker periods), applied to nonstandard test functions. This gives a new proof of the celebrated result of Waldspurger on toric periods, and suggests a new way of comparing trace formulas, with some analogies to Langlands’ ‘Beyond Endoscopy’ program.
A concept analysis in relation to the cultural competency of the palliative care workforce in meeting the needs of young people from South Asian cultures
Authors: Brown Erica , Franklin Anita , Coad Jane
Published: April 2017

Objective:

Our aims were to report an analysis of the concept of cultural competency and to explore how the cultural competency of the palliative care workforce impacts the holistic care of young people with palliative care needs from South Asian cultures.

Method:

Using keywords, we searched the online databases MEDLINE, CINAHL, ScienceDirect, and PubMed from January of 1990 through to December of 2016. Some 1543 articles were retrieved, and inclusion and exclusion criteria were applied. A total of 38 papers were included in the concept analysis. The data were analyzed using Coad's (2002) adapted framework based on Rodgers's (1989) evolutionary concept analysis, focusing on the attributes, antecedents, consequences, and related terms in relation to culturally competent care. A model case of culturally competent care was also constructed.

Results:

The literature provides evidence that the concept of culturally competent care is a complex one, which is often expressed ambiguously. In addition, there is a paucity of research that involves service users as experts in defining their own needs and assessing their experiences related to cultural care.

Significance of Results:

Cultural care should be integral to holistic patient care, irrespective of a person's race or ethnicity. There is an urgent need to involve young BAME patients with palliative care needs and their families in the development of a robust tool to assess cultural competency in clinical practice.
Association between burnout and cortisol secretion, perceived stress, and psychopathology in palliative care unit health professionals
Authors: Fernández-Sánchez José Carlos , Pérez-Mármol José Manuel , Blásquez Antonia , Santos-Ruiz Ana María , Peralta-Ramírez María Isabel
Published: April 2017

Objective:

A high incidence of burnout has been reported in health professionals working in palliative care units. Our present study aims to determine whether there are differences in the secretion of salivary cortisol between palliative care unit health professionals with and without burnout, and to elucidate whether there is a relationship between burnout syndrome and perceived stress and psychopathological status in this population.

Method:

A total of 69 health professionals who met the inclusion criteria participated in our study, including physicians, nurses, and nursing assistants. Some 58 were women (M = 29.65 years, SD = 8.64) and 11 men (M = 35.67 years, SD = 11.90). The level of daily cortisol was registered in six measurements taken over the course of a workday. Burnout syndrome was evaluated with the Maslach Burnout Inventory–Human Services Survey (MBI–HSS), the level of perceived stress was measured using the Perceived Stress Scale, and psychopathological status was gauged using the SCL–90–R Symptoms Inventory.

Results:

There were statistically significant differences in secretion of cortisol in professionals with high scores on a single subscale of the MBI–HSS [F(3.5) = 2.48, p < 0.03]. This effect was observed 15–30 minutes after waking up (p < 0.01) and at bedtime (p < 0.06). Moreover, the professionals with burnout showed higher scores on the psychopathology and stress subscales than professionals without it.

Significance of results:

A higher score in any dimension of the burnout syndrome in palliative care unit health professionals seems to be related to several physiological and psychological parameters. These findings may be relevant for further development of our understanding of the relationship between levels of burnout and cortisol secretion in the health workers in these units.
Studies of the Seasonal Pattern of Multiple Maternities
Authors: Fellman Johan
Published: April 2017

The seasonality of population data has been of great interest in demographic studies. When seasonality is analyzed,the population at riskplays a central role. In a study of the monthly number of births and deaths, the population at risk is the product of the size of the population and the length of the month. Usually, the population can be assumed to be constant, and consequently, the population at risk is proportional to the length of the month. Hence, the number of cases per day has to be analyzed. If one studies the seasonal variation in twin or multiple maternities, the population at risk is the total number of monthly confinements, and the study should be based on the rates of the multiple maternities. Consequently, if one considers monthly twinning rates, the monthly number of birth data is eliminated and one obtains an unaffected seasonality measure of the twin maternities. The strength of the seasonality is measured by a chi-squared test or by the standard deviation. When seasonal models are applied, one must pay special attention to how well the model fits the data. If the goodness of fit is poor, it can erroneously result in a statement that the seasonality is slight, although the observed seasonal fluctuations are marked.
Flavored little cigar smoke induces cytotoxicity and apoptosis in airway epithelia
Authors: Ghosh Arunava , Nethery Rachel C , Herring Amy H , Tarran Robert
Published: April 2017

Addition of flavors reduces the harsh taste of tobacco, facilitating the initiation and maintenance of addiction among youths. Flavored cigarettes (except menthol) are now banned. However, the legislation on little cigars remains unclear and flavored little cigars are currently available for purchase. Since inhaled tobacco smoke directly exerts toxic effects on the lungs, we tested whether non-flavored and flavored little cigar smoke exposure had the potential for harm in cultured pulmonary epithelia. We cultured Calu-3 lung epithelia on both 96-well plates and at the air–liquid interface and exposed them to smoke from non-flavored Swisher Sweets and flavored (sweet cherry, grape, menthol, peach and strawberry) Swisher Sweets little cigars. Irrespective of flavor, acute little cigar smoke exposure (10×35 ml puffs) significantly increased cell death and decreased the percentage of live cells. Chronic exposure (10×35 ml puffs per day for 4 days) of smoke to Calu-3 cultures significantly increased lactate dehydrogenase release, further indicating toxicity. To determine whether this exposure was associated with increased cell death/apoptosis, a protein array was used. Chronic exposure to smoke from all types of little cigars induced the activation of the two major apoptosis pathways, namely the intrinsic (mitochondrial-mediated) and the extrinsic (death receptor-mediated) pathways. Both flavored and non-flavored little cigar smoke caused similar levels of toxicity and activation of apoptosis, suggesting that flavored and non-flavored little cigars are equally harmful. Hence, the manufacture, advertisement, sale and use of both non-flavored and flavored little cigars should be strictly controlled.
DNA single-strand break-induced DNA damage response causes heart failure
Authors: Higo Tomoaki , Naito Atsuhiko T. , Sumida Tomokazu , Shibamoto Masato , Okada Katsuki , Nomura Seitaro , Nakagawa Akito , Yamaguchi Toshihiro , Sakai Taku , Hashimoto Akihito , Kuramoto Yuki , Ito Masamichi , Hikoso Shungo , Akazawa Hiroshi , Lee Jong-Kook , Shiojima Ichiro , McKinnon Peter J. , Sakata Yasushi , Komuro Issei
Published: April 2017

The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure.
Photostriction of strontium ruthenate
Authors: Wei Tzu-Chiao , Wang Hsin-Ping , Liu Heng-Jui , Tsai Dung-Sheng , Ke Jr-Jian , Wu Chung-Lun , Yin Yu-Peng , Zhan Qian , Lin Gong-Ru , Chu Ying-Hao , He Jr-Hau
Published: April 2017

Transition metal oxides with a perovskite crystal structure exhibit a variety of physical properties associated with the lattice. Among these materials, strontium ruthenate (SrRuO3) displays unusually strong coupling of charge, spin and lattice degrees of freedom that can give rise to the photostriction, that is, changes in the dimensions of material due to the absorption of light. In this study, we observe a photon-induced strain as high as 1.12% in single domain SrRuO3, which we attribute to a nonequilibrium of phonons that are a result of the strong interaction between the crystalline lattice and electrons excited by light. In addition, these light-induced changes in the SrRuO3 lattice affect its electrical resistance. The observation of both photostriction and photoresistance in SrRuO3 suggests the possibility of utilizing the mechanical and optical functionalities of the material for next-generation optoelectronics, such as remote switches, light-controlled elastic micromotors, microactuators and other optomechanical systems.
TCRP1 promotes NIH/3T3 cell transformation by over-activating PDK1 and AKT1
Authors: Wang C , Liu H , Qiu Q , Zhang Z , Gu Y , He Z
Published: April 2017

Tongue cancer resistance-related protein 1 (TCRP1) gene was first cloned from the multidrug resistance tongue cancer cell (Tca8113/pingyangmycin) in our lab. Our precious studies demonstrated that TCRP1 was involving in chemotherapy and radiotherapy resistance of tongue cancer cells, lung cancer cells and ovarian cancer cells. In this study, we showed that TCRP1 overexpression promotes cell transformation and tumorigenesis through hyperphosphorylation of the oncogenic kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT1, whereas inhibition of PDK1 by OSU-03012 or PDK1 small interfering RNA reversed TCRP1-mediated cell transformation. Importantly, TCRP1 was able to directly interact with PDK1, and 93–107 amino-acid and 109–124 amino-acid sites of TCRP1 were the common binding domain of PDK1. Moreover, in line with its oncogenic activity, we found that TCRP1 is often overexpressed in human in lung cancer, glioma, ovarian cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, stomach cancer and tongue carcinoma tissues. Spearman correlation analysis showed that the expression of TCRP1 has a positive correlation with p-PDK1, as well as p-AKT1 in lung cancer and gliomas tissues. Thus, TCRP1 may be a candidate as human oncoprotein that promotes cancer development by activation of PDK1/AKT1 signaling.
Gravireceptors in eukaryotes—a comparison of case studies on the cellular level
Authors: Häder Donat-P. , Braun Markus , Grimm Daniela , Hemmersbach Ruth
Published: April 2017

We have selected five evolutionary very different biological systems ranging from unicellular protists via algae and higher plants to human cells showing responses to the gravity vector of the Earth in order to compare their graviperception mechanisms. All these systems use a mass, which may either by a heavy statolith or the whole content of the cell heavier than the surrounding medium to operate on a gravireceptor either by exerting pressure or by pulling on a cytoskeletal element. In many cases the receptor seems to be a mechanosensitive ion channel activated by the gravitational force which allows a gated ion flux across the membrane when activated. This has been identified in many systems to be a calcium current, which in turn activates subsequent elements of the sensory transduction chain, such as calmodulin, which in turn results in the activation of ubiquitous enzymes, gene expression activation or silencing. Naturally, the subsequent responses to the gravity stimulus differ widely between the systems ranging from orientational movement and directed growth to physiological reactions and adaptation to the environmental conditions.
Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
Authors: Al-Baghdadi Rana J. T. , Nikonorova Inna A. , Mirek Emily T. , Wang Yongping , Park Jinhee , Belden William J. , Wek Ronald C. , Anthony Tracy G.
Published: April 2017

The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2−/−, and Atf4−/− mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4+/− mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4−/− or Atf4+/− mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4−/− mice treated with asparaginase. Conclusions: GCN2 and ATF4 serve complementary roles in the hepatic response to asparaginase. GCN2 functions to limit inflammation and mTORC1 signaling whereas ATF4 serves to limit the amino acid response and prevent ER stress during amino acid depletion by asparaginase.
Genome-wide fitness analyses of the foodborne pathogen Campylobacter jejuni in in vitro and in vivo models
Authors: de Vries Stefan P. , Gupta Srishti , Baig Abiyad , Wright Elli , Wedley Amy , Jensen Annette Nygaard , Lora Lizeth LaCharme , Humphrey Suzanne , Skovgård Henrik , Macleod Kareen , Pont Elsa , Wolanska Dominika P. , L’Heureux Joanna , Mobegi Fredrick M. , Smith David G. E. , Everest Paul , Zomer Aldert , Williams Nicola , Wigley Paul , Humphrey Thomas , Maskell Duncan J. , Grant Andrew J.
Published: April 2017

Campylobacter is the most common cause of foodborne bacterial illness worldwide. Faecal contamination of meat, especially chicken, during processing represents a key route of transmission to humans. There is a lack of insight into the mechanisms driving C. jejuni growth and survival within hosts and the environment. Here, we report a detailed analysis of C. jejuni fitness across models reflecting stages in its life cycle. Transposon (Tn) gene-inactivation libraries were generated in three C. jejuni strains and the impact on fitness during chicken colonisation, survival in houseflies and under nutrient-rich and –poor conditions at 4 °C and infection of human gut epithelial cells was assessed by Tn-insertion site sequencing (Tn-seq). A total of 331 homologous gene clusters were essential for fitness during in vitro growth in three C. jejuni strains, revealing that a large part of its genome is dedicated to growth. We report novel C. jejuni factors essential throughout its life cycle. Importantly, we identified genes that fulfil important roles across multiple conditions. Our comprehensive screens showed which flagella elements are essential for growth and which are vital to the interaction with host organisms. Future efforts should focus on how to exploit this knowledge to effectively control infections caused by C. jejuni.
Calcium-Sensing Receptor Antagonist NPS 2143 Restores Amyloid Precursor Protein Physiological Non-Amyloidogenic Processing in Aβ-Exposed Adult Human Astrocytes
Authors: Chiarini Anna , Armato Ubaldo , Liu Daisong , Dal Prà Ilaria
Published: April 2017

Physiological non-amyloidogenic processing (NAP) of amyloid precursor holoprotein (hAPP) by α-secretases (e.g., ADAM10) extracellularly sheds neurotrophic/neuroprotective soluble (s)APPα and precludes amyloid-β peptides (Aβs) production via β-secretase amyloidogenic processing (AP). Evidence exists that Aβs interact with calcium-sensing receptors (CaSRs) in human astrocytes and neurons, driving the overrelease of toxic Aβ42/Aβ42-os (oligomers), which is completely blocked by CaSR antagonist (calcilytic) NPS 2143. Here, we investigated the mechanisms underlying NPS 2143 beneficial effects in human astrocytes. Moreover, because Alzheimer’s disease (AD) involves neuroinflammation, we examined whether NPS 2143 remained beneficial when both fibrillary (f)Aβ25–35 and a microglial cytokine mixture (CMT) were present. Thus, hAPP NAP prevailed over AP in untreated astrocytes, which extracellularly shed all synthesized sAPPα while secreting basal Aβ40/42 amounts. Conversely, fAβ25–35 alone dramatically reduced sAPPα extracellular shedding while driving Aβ42/Aβ42-os oversecretion that CMT accelerated but not increased, despite a concurring hAPP overexpression. NPS 2143 promoted hAPP and ADAM10 translocation to the plasma membrane, thereby restoring sAPPα extracellular shedding and fully suppressing any Aβ42/Aβ42-os oversecretion, but left hAPP expression unaffected. Therefore, as anti-AD therapeutics calcilytics support neuronal viability by safeguarding astrocytes neurotrophic/neuroprotective sAPPα shedding, suppressing neurons and astrocytes Aβ42/Aβ42-os build-up/secretion, and remaining effective even under AD-typical neuroinflammatory conditions.
ER retention receptor, MoERR1 is required for fungal development and pathogenicity in the rice blast fungus, Magnaporthe oryzae
Authors: Goh Jaeduk , Jeon Junhyun , Lee Yong-Hwan
Published: April 2017

ER retention receptor is a seven trans-membrane protein that plays pivotal roles in function and integrity of endoplasmic reticulum (ER). Insertional mutagenesis of Magnaporthe oryzae identified MoERR1 as a pathogenicity gene encoding putative ER retention receptor orthologous to ERD2 in Saccharomyces cerevisiae. Search through the genome identified that M. oryzae possesses another ortholog of ERD2, which is designated as MoERR2. When MoERR1 and MoERR2 were tagged with GFP, both were localized to ER. Targeted disruption of MoERR1 showed pleiotropic effects on phenotypes, while deletion of MoERR2 had no effect on phenotypes we examined. The disruption mutant of MoERR1 showed growth retardation and produced significantly reduced number of conidia with aberrant morphology. Appressoria from the mutant were unable to penetrate into plant tissues presumably due to defect in cell wall integrity, thereby rendering the mutant non-pathogenic. The MoERR1 mutant also appeared to display abnormal ER structure and mis-regulation of genes involved in chaperone function and unfolded protein response under ER stress condition. Taken together, these results suggest that MoERR1 is a ER retention receptor required for function and integrity of ER, and that MoERR1-mediated ER functionalities are essential for fungal development and pathogenesis.
Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways
Authors: Janjetovic Zorica , Jarrett Stuart G. , Lee Elizabeth F. , Duprey Cory , Reiter Russel J. , Slominski Andrzej T.
Published: April 2017

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing of NRF2 using siRNA diminished the protective effects of melatonin, while the membrane melatonin receptors (MT1 or MT2) did not change the activities of either melatonin or its derivatives. Melatonin and its metabolites enhanced the DNA repair in melanocytes exposed to UVB and stimulated expression of p53 phosphorylated at Ser-15. In conclusion, melatonin and its metabolites protect melanocytes from UVB-induced DNA damage and oxidative stress through activation of NRF2-dependent pathways; these actions are independent of an effect on the classic membrane melatonin receptors. Thus, melatonin and its derivatives can serve as excellent protectors of melanocytes against UVB-induced pathology.
Lamins and nesprin-1 mediate inside-out mechanical coupling in muscle cell precursors through FHOD1
Authors: Schwartz Christine , Fischer Martina , Mamchaoui Kamel , Bigot Anne , Lok Thevy , Verdier Claude , Duperray Alain , Michel Richard , Holt Ian , Voit Thomas , Quijano-Roy Suzanna , Bonne Gisèle , Coirault Catherine
Published: April 2017

LINC complexes are crucial for the response of muscle cell precursors to the rigidity of their environment, but the mechanisms explaining this behaviour are not known. Here we show that pathogenic mutations in LMNA or SYNE-1 responsible for severe muscle dystrophies reduced the ability of human muscle cell precursors to adapt to substrates of different stiffness. Plated on muscle-like stiffness matrix, mutant cells exhibited contractile stress fibre accumulation, increased focal adhesions, and higher traction force than controls. Inhibition of Rho-associated kinase (ROCK) prevented cytoskeletal defects, while inhibiting myosin light chain kinase or phosphorylation of focal adhesion kinase was ineffective. Depletion or inactivation of a ROCK-dependent regulator of actin remodelling, the formin FHOD1, largely rescued morphology in mutant cells. The functional integrity of lamin and nesprin-1 is thus required to modulate the FHOD1 activity and the inside-out mechanical coupling that tunes the cell internal stiffness to match that of its soft, physiological-like environment.
Grb2 carboxyl-terminal SH3 domain can bivalently associate with two ligands, in an SH3 dependent manner
Authors: Arya Richa , Dangi Rohit Singh , Makwana Pinakin K. , Kumar Ambrish , Upadhyay Santosh Kumar , Sundd Monica
Published: April 2017

Src homology domain containing leukocyte protein of 65 kDa (SLP65), the growth factor receptor binding protein 2 (Grb2), and the guanine nucleotide exchange factor for the Rho family GTPases (Vav), self associate in unstimulated B cells as components of the preformed B cell receptor transducer module, in an SH3-dependent manner. The complex enables the B cell to promptly respond to BCR aggregation, resulting in signal amplification. It also facilitates Vav translocation to the membrane rafts, for activation. Here we uncover the molecular mechanism by which the complex may be formed in the B cell. The C-terminal SH3 domain (SH3C) of Grb2 bivalently interacts with the atypical non-PxxP proline rich region of SLP65, and the N-terminal SH3 domain (SH3N) of Vav, both the interactions crucial for the proper functioning of the B cell. Most surprisingly, the two ligands bind the same ligand binding site on the surface of Grb2 SH3C. Addition of SLP65 peptide to the Grb2-Vav complex abrogates the interaction completely, displacing Vav. However, the addition of Vav SH3N to the SLP65-Grb2 binary complex, results in a trimeric complex. Extrapolating these results to thein vivoconditions, Grb2 should bind the SLP65 transducer module first, and then Vav should associate.
Elasticity and Stability of Clathrate Hydrate: Role of Guest Molecule Motions
Authors: Jia Jihui , Liang Yunfeng , Tsuji Takeshi , Murata Sumihiko , Matsuoka Toshifumi
Published: April 2017

Molecular dynamic simulations were performed to determine the elastic constants of carbon dioxide (CO2) and methane (CH4) hydrates at one hundred pressure–temperature data points, respectively. The conditions represent marine sediments and permafrost zones where gas hydrates occur. The shear modulus and Young’s modulus of the CO2 hydrate increase anomalously with increasing temperature, whereas those of the CH4 hydrate decrease regularly with increase in temperature. We ascribe this anomaly to the kinetic behavior of the linear CO2 molecule, especially those in the small cages. The cavity space of the cage limits free rotational motion of the CO2 molecule at low temperature. With increase in temperature, the CO2 molecule can rotate easily, and enhance the stability and rigidity of the CO2 hydrate. Our work provides a key database for the elastic properties of gas hydrates, and molecular insights into stability changes of CO2 hydrate from high temperature of ~5 °C to low decomposition temperature of ~−150 °C.
A humanized mouse model identifies key amino acids for low immunogenicity of H7N9 vaccines
Authors: Wada Yamato , Nithichanon Arnone , Nobusawa Eri , Moise Leonard , Martin William D. , Yamamoto Norio , Terahara Kazutaka , Hagiwara Haruhisa , Odagiri Takato , Tashiro Masato , Lertmemongkolchai Ganjana , Takeyama Haruko , De Groot Anne S. , Ato Manabu , Takahashi Yoshimasa
Published: April 2017

Influenza vaccines of H7N9 subtype are consistently less immunogenic in humans than vaccines developed for other subtypes. Although prior immunoinformatic analysis identified T-cell epitopes in H7 hemagglutinin (HA) which potentially enhance regulatory T cell response due to conservation with the human genome, the links between the T-cell epitopes and low immunogenicity of H7 HA remains unknown due to the lack of animal models reproducing the response observed in humans. Here, we utilized a humanized mouse model to recapitulate the low immunogenicity of H7 HA. Our analysis demonstrated that modification of a single H7 epitope by changing 3 amino acids so that it is homologous with a known H3 immunogenic epitope sequence significantly improved the immunogenicity of the H7 HA in the humanized mouse model, leading to a greater than 4-fold increase in HA-binding IgG responses. Thus, we provide experimental evidence for the important contribution of this H7-specific T cell epitope in determining the immunogenicity of an influenza vaccine. Furthermore, this study delineates strategies that can be used for screening and selecting vaccine strains using immunoinformatics tools and a humanized mouse model.
Facile control of nanoporosity in Cellulose Acetate using Nickel(II) nitrate additive and water pressure treatment for highly efficient battery gel separators
Authors: Lee Woong Gi , Kim Do Hyeong , Jeon Woo Cheol , Kwak Sang Kyu , Kang Seok Ju , Kang Sang Wook
Published: April 2017

We succeed in fabricating nearly straight nanopores in cellulose acetate (CA) polymers for use as battery gel separators by utilizing an inorganic hexahydrate (Ni(NO3)2·6H2O) complex and isostatic water pressure treatment. The continuous nanopores are generated when the polymer film is exposed to isostatic water pressure after complexing the nickel(II) nitrate hexahydrate (Ni(NO3)2·6H2O) with the CA. These results can be attributed to the manner in which the polymer chains are weakened because of the plasticization effect of the Ni(NO3)2·6H2O that is incorporated into the CA. Furthermore, we performed extensive molecular dynamics simulation for confirming the interaction between electrolyte and CA separator. The well controlled CA membrane after water pressure treatment enables fabrication of highly reliable cell by utilizing 2032-type coin cell structure. The resulting cell performance exhibits not only the effect of the physical morphology of CA separator, but also the chemical interaction of electrolyte with CA polymer which facilitates the Li-ion in the cell.
Families of stable solitons and excitations in the PT-symmetric nonlinear Schrödinger equations with position-dependent effective masses
Authors: Chen Yong , Yan Zhenya , Mihalache Dumitru , Malomed Boris A.
Published: April 2017

Since the parity-time-($$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
-) symmetric quantum mechanics was put forward, fundamental properties of some linear and nonlinear models with $$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
-symmetric potentials have been investigated. However, previous studies of $$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
-symmetric waves were limited to constant diffraction coefficients in the ambient medium. Here we address effects of variable diffraction coefficient on the beam dynamics in nonlinear media with generalized $$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
-symmetric Scarf-II potentials. The broken linear $$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
symmetry phase may enjoy a restoration with the growing diffraction parameter. Continuous families of one- and two-dimensional solitons are found to be stable. Particularly, some stable solitons are analytically found. The existence range and propagation dynamics of the solitons are identified. Transformation of the solitons by means of adiabatically varying parameters, and collisions between solitons are studied too. We also explore the evolution of constant-intensity waves in a model combining the variable diffraction coefficient and complex potentials with globally balanced gain and loss, which are more general than $$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
-symmetric ones, but feature similar properties. Our results may suggest new experiments for $$\pmb{\mathscr{P}}\pmb{\mathscr{T}}$$
P
T
-symmetric nonlinear waves in nonlinear nonuniform optical media.
Neural coding of prior expectations in hierarchical intention inference
Authors: Chambon Valerian , Domenech Philippe , Jacquet Pierre O. , Barbalat Guillaume , Bouton Sophie , Pacherie Elisabeth , Koechlin Etienne , Farrer Chlöé
Published: April 2017

The ability to infer other people’s intentions is crucial for successful human social interactions. Such inference relies on an adaptive interplay of sensory evidence and prior expectations. Crucially, this interplay would also depend on the type of intention inferred, i.e., on how abstract the intention is. However, what neural mechanisms adjust the interplay of prior and sensory evidence to the abstractness of the intention remains conjecture. We addressed this question in two separate fMRI experiments, which exploited action scenes depicting different types of intentions (Superordinate vs. Basic; Social vs. Non-social), and manipulated both prior and sensory evidence. We found that participants increasingly relied on priors as sensory evidence became scarcer. Activity in the medial prefrontal cortex (mPFC) reflected this interplay between the two sources of information. Moreover, the more abstract the intention to infer (Superordinate > Basic, Social > Non-Social), the greater the modulation of backward connectivity between the mPFC and the temporo-parietal junction (TPJ), resulting in an increased influence of priors over the intention inference. These results suggest a critical role for the fronto-parietal network in adjusting the relative weight of prior and sensory evidence during hierarchical intention inference.
Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts
Authors: Harrach Saliha , Edemir Bayram , Schmidt-Lauber Christian , Pap Thomas , Bertrand Jessica , Ciarimboli Giuliano
Published: April 2017

Recent therapeutic approaches of rheumatoid arthritis (RA) address the use of small molecules such as tyrosine kinase inhibitors (TKIs). However, the TKIs developed to date have important side effects and/or scarce efficacy in inflammatory diseases such as RA. Since intracellular effective TKIs must enter the cell to reach their intracellular targets, here we investigated the interaction of the TKI saracatinib, a dual inhibitor of c-Src and c-Abl signaling, with transporters for organic cations as well as the role of these transporters for the biological effect of saracatinib in human RA-synovial fibroblasts (hRASF). Saracatinib significantly reduced proliferation of hRASF. The cellular saracatinib uptake was mainly dependent on the human novel organic cation transporter 1 (hOCTN1), which showed the highest apparent affinity for saracatinib among all other transporters for organic cations analyzed here. In hRASF, saracatinib biologic function was dependent on hOCTN1. Further analysis showed that disease specific factors (pH, inflammatory cytokines such as TNFα) regulated saracatinib uptake in hRASF. The knowledge of which transporters mediate the specific uptake of TKIs in target cells and of how the expression and function of such transporters are regulated in RA is of highest priority to develop effective drugs for successful therapy with minimal side-effects.
Left Ventricular Stiffness in Adolescents and Young Adults with Repaired Tetralogy of Fallot
Authors: Yu Clement Kwong-man , Wong Wilfred Hing-sang , Li Vivian Wing-yi , Cheung Yiu-fai
Published: April 2017

Left ventricular (LV) remodeling after tetralogy of Fallot (TOF) repair may influence LV stiffness. We hypothesized that LV stiffness is altered after TOF repair and related to myocardial calibrated integrated backscatter (cIB) and LV diastolic myocardial deformation. Seventy-seven TOF patients and 80 controls were studied. LV stiffness was assessed by diastolic wall strain (DWS) as defined by (LVPWsystole-LVPWdiastole)/LVPWsystole, where LVPW is LV posterior wall thickness, and stiffness index as defined by (E/e/LV end-diastolic dimension), where E and e are respectively early diastolic transmitral inflow and mitral annular velocities. Septal and LVPW cIB and LV diastolic strain rates were determined. Patients had significantly lower DWS (p < 0.001), higher stiffness index (p < 0.001), and greater cIB (p < 0.001). LV DWS correlated negatively with LV stiffness index (r = −0.31, p < 0.001), septal cIB (r = −0.21, p = 0.01), E/e ratio (r = −0.30, p < 0.001) and RV end-diastolic area (r = −0.31, p < 0.001), and positively with LV early (r = 0.33, p < 0.001) and late (r = 0.20, p = 0.01) diastolic strain rates and RV fractional area change (FAC) (r = 0.24, p = 0.003). Multivariate analysis revealed E/e (β = −0.26, p = 0.008), RV end-diastolic area (β = −0.20, p = 0.02), and RV FAC (β = 0.18, p = 0.01) as significant correlates of DWS. Left ventricular stiffening occurs after TOF repair and is related to impaired LV diastolic myocardial deformation, myocardial cIB, and RV volume overload.
Revisiting the IGF-1R as a breast cancer target
Authors: Ekyalongo Roudy Chiminch , Yee Douglas
Published: April 2017

The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3′-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions.
A feasible strategy to balance the crystallinity and specific surface area of metal oxide nanocrystals
Authors: Zhang Q. P. , Xu X. N. , Liu Y. T. , Xu M. , Deng S. H. , Chen Y. , Yuan H. , Yu F. , Huang Y. , Zhao K. , Xu S. , Xiong G.
Published: April 2017

Practical, efficient synthesis of metal oxide nanocrystals with good crystallinity and high specific surface area by a modified polymer-network gel method is demonstrated, taking ZnO nanocrystals as an example. A novel stepwise heat treatment yields significant improvement in crystal quality. Such nanophase materials can effectively degrade common organic dyes under solar radiation and can perform very well in photo-assisted detection of NO2 gas. Other typical metal oxide nanocrystals with good crystallinity and high specific surface area were also synthesized successfully under similar conditions. This work provides a general strategy for the synthesis of metal oxide nanocrystals, balancing the crystallinity and specific surface area.
Effects of Chinese Medicine as Adjunct Medication for Adjuvant Chemotherapy Treatments of Non-Small Cell Lung Cancer Patients
Authors: Jiao Lijing , Dong Changsheng , Liu Jiaxiang , Chen Zhiwei , Zhang Lei , Xu Jianfang , Shen Xiaoyong , Che Jiaming , Yang Yi , Huang Hai , Li Hegen , Sun Jianli , Jiang Yi , Mao Zhujun , Chen Peiqi , Gong Yabin , Jin Xiaolin , Xu Ling
Published: April 2017

The aim was to evaluate the effects of traditional Chinese medicine (TCM) as a combination medication with adjuvant chemotherapy on postoperative early stage non-small cell lung cancer (NSCLC) patients. The 314 patients with completely resected stage IB, II or IIIA cancers were assigned into vinorelbine plus cisplatin/carboplatin (NP/NC) (control,n = 158) and NP/NC with additional TCM (intervention,n = 156) groups. The primary endpoint was QOL scores; secondary endpoints were the toxicity and safety of the regimens. The NP/NC regimen caused mild (grade 1 or 2) non-hematologic toxic effects in the patients comprising vomiting (43.6%), fatigue (36.9%), pain (23%), dry mouth (27.6%) and diarrhea (7.9%). The incidence of adverse events was significantly lower in the intervention group than in the control group (0.57%vs4.02%,P = 0.037). Transient severe (grade 3 or 4) hematological toxic effects occurred less often (hemoglobin reduction (11.9vs22.5 percent) and total bilirubin increased (to 42.1 vs 46.2%) in the intervention compared to the control group during the 2nd chemotherapy cycle. When combined with adjuvant chemotherapy, TCM led to partial relief of symptoms in addition to a reduction of side-effects and adverse events caused by the NP/NC regimens.