bluuebunny/crossref_metadata_2025 huggingface dataset:
NDRG2 contributes to cisplatin sensitivity through modulation of BAK-to-Mcl-1 ratio
Authors: Park Soojong , Oh Sang-Seok , Lee Ki Won , Lee Yeon-Kyeong , Kim Nae Yu , Kim Joo Heon , Yoo Jiyun , Kim Kwang Dong
Published: January 2018

The downregulation of N-Myc downstream-regulated gene 2 (NDRG2) is known to be associated with the progression and poor prognosis of several cancers. Sensitivity to anti-cancer may be associated with a good prognosis in cancer patients, and NDRG2, which is induced by p53, sensitizes the cells to chemotherapy. However, the unique function of NDRG2 as an inducer of apoptosis under chemotreatment has not been sufficiently studied. In this study, we investigated the role of NDRG2 in chemo-sensitivity, focusing on cisplatin in U937 histiocytic lymphoma, which has the loss-of-functional mutation in p53. NDRG2 promoted the sensitivity to cisplatin through the modulation of the BAK-to-Mcl-1 ratio. The degradation of Mcl-1 and increase in BAK were mediated by JNK activation and the eIF2α/p-eIF2α pathway, respectively, which depended on PKR activation in NDRG2-overexpressed U937 (U937-NDRG2) cells. NOX5 was highly expressed in U937-NDRG2 cells and contributed to ROS production after cisplatin treatment. ROS scavenging or NOX5-knockdown successfully inhibited the sensitivity of U937-NDRG2 cells to cisplatin. Taken together, these findings indicate that NDRG2 contributed to the increased sensitivity to ciplatin through the modulation of Bak-to-Mcl-1 ratio regulated by NOX5-ROS-PKR pathway; therefore, we suggest that NDRG2 may be a molecular target for improving the efficacy of drug treatment in cancer patients.
Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae
Authors: Benjak Andrej , Avanzi Charlotte , Singh Pushpendra , Loiseau Chloé , Girma Selfu , Busso Philippe , Fontes Amanda N. Brum , Miyamoto Yuji , Namisato Masako , Bobosha Kidist , Salgado Claudio G. , da Silva Moisés B. , Bouth Raquel C. , Frade Marco A. C. , Filho Fred Bernardes , Barreto Josafá G. , Nery José A. C. , Bührer-Sékula Samira , Lupien Andréanne , Al-Samie Abdul R. , Al-Qubati Yasin , Alkubati Abdul S. , Bretzel Gisela , Vera-Cabrera Lucio , Sakho Fatoumata , Johnson Christian R. , Kodio Mamoudou , Fomba Abdoulaye , Sow Samba O. , Gado Moussa , Konaté Ousmane , Stefani Mariane M. A. , Penna Gerson O. , Suffys Philip N. , Sarno Euzenir Nunes , Moraes Milton O. , Rosa Patricia S. , Baptista Ida M. F. Dias , Spencer John S. , Aseffa Abraham , Matsuoka Masanori , Kai Masanori , Cole Stewart T.
Published: January 2018

Leprosy is a chronic human disease caused by the yet-uncultured pathogenMycobacterium leprae. Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still reported annually. Here, we obtainM. lepraegenome sequences from DNA extracted directly from patients’ skin biopsies using a customized protocol. Comparative and phylogenetic analysis of 154 genomes from 25 countries provides insight into evolution and antimicrobial resistance, uncovering lineages and phylogeographic trends, with the most ancestral strains linked to the Far East. In addition to known MDT-resistance mutations, we detect other mutations associated with antibiotic resistance, and retrace a potential stepwise emergence of extensive drug resistance in the pre-MDT era. Some of the previously undescribed mutations occur in genes that are apparently subject to positive selection, and two of these (ribD,fadD9) are restricted to drug-resistant strains. Finally, nonsense mutations in thenthexcision repair gene are associated with greater sequence diversity and drug resistance.
Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses
Authors: Deng Lei , Mohan Teena , Chang Timothy Z. , Gonzalez Gilbert X. , Wang Ye , Kwon Young-Man , Kang Sang-Moo , Compans Richard W. , Champion Julie A. , Wang Bao-Zhong
Published: January 2018

Current influenza vaccines provide limited protection against circulating influenza A viruses. A universal influenza vaccine will eliminate the intrinsic limitations of the seasonal flu vaccines. Here we report methodology to generate double-layered protein nanoparticles as a universal influenza vaccine. Layered nanoparticles are fabricated by desolvating tetrameric M2e into protein nanoparticle cores and coating these cores by crosslinking headless HAs. Representative headless HAs of two HA phylogenetic groups are constructed and purified. Vaccinations with the resulting protein nanoparticles in mice induces robust long-lasting immunity, fully protecting the mice against challenges by divergent influenza A viruses of the same group or both groups. The results demonstrate the importance of incorporating both structure-stabilized HA stalk domains and M2e into a universal influenza vaccine to improve its protective potency and breadth. These potent disassemblable protein nanoparticles indicate a wide application in protein drug delivery and controlled release.
T cells specific for post-translational modifications escape intrathymic tolerance induction
Authors: Raposo Bruno , Merky Patrick , Lundqvist Christina , Yamada Hisakata , Urbonaviciute Vilma , Niaudet Colin , Viljanen Johan , Kihlberg Jan , Kyewski Bruno , Ekwall Olov , Holmdahl Rikard , Bäcklund Johan
Published: January 2018

Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism.
Shielding and activation of a viral membrane fusion protein
Authors: Halldorsson Steinar , Li Sai , Li Mengqiu , Harlos Karl , Bowden Thomas A. , Huiskonen Juha T.
Published: January 2018

Entry of enveloped viruses relies on insertion of hydrophobic residues of the viral fusion protein into the host cell membrane. However, the intermediate conformations during fusion remain unknown. Here, we address the fusion mechanism of Rift Valley fever virus. We determine the crystal structure of the Gn glycoprotein and fit it with the Gc fusion protein into cryo-electron microscopy reconstructions of the virion. Our analysis reveals how the Gn shields the hydrophobic fusion loops of the Gc, preventing premature fusion. Electron cryotomography of virions interacting with membranes under acidic conditions reveals how the fusogenic Gc is activated upon removal of the Gn shield. Repositioning of the Gn allows extension of Gc and insertion of fusion loops in the outer leaflet of the target membrane. These data show early structural transitions that enveloped viruses undergo during host cell entry and indicate that analogous shielding mechanisms are utilized across diverse virus families.
Author Correction: Long-term carbon sink in Borneo’s forests halted by drought and vulnerable to edge effects
Authors: Qie Lan , Lewis Simon L. , Sullivan Martin J. P. , Lopez-Gonzalez Gabriela , Pickavance Georgia C. , Sunderland Terry , Ashton Peter , Hubau Wannes , Abu Salim Kamariah , Aiba Shin-Ichiro , Banin Lindsay F. , Berry Nicholas , Brearley Francis Q. , Burslem David F. R. P. , Dančák Martin , Davies Stuart J. , Fredriksson Gabriella , Hamer Keith C. , Hédl Radim , Kho Lip Khoon , Kitayama Kanehiro , Krisnawati Haruni , Lhota Stanislav , Malhi Yadvinder , Maycock Colin , Metali Faizah , Mirmanto Edi , Nagy Laszlo , Nilus Reuben , Ong Robert , Pendry Colin A. , Poulsen Axel Dalberg , Primack Richard B. , Rutishauser Ervan , Samsoedin Ismayadi , Saragih Bernaulus , Sist Plinio , Ferry Slik J. W. , Sukri Rahayu Sukmaria , Svátek Martin , Tan Sylvester , Tjoa Aiyen , van Nieuwstadt Mark , Vernimmen Ronald R. E. , Yassir Ishak , Kidd Petra Susan , Fitriadi Muhammad , Ideris Nur Khalish Hafizhah , Serudin Rafizah Mat , Abdullah Lim Layla Syaznie , Saparudin Muhammad Shahruney , Phillips Oliver L.
Published: January 2018

The original version of this Article contained an error in the third sentence of the abstract and incorrectly read “Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha−1 year−1 (95% CI 0.14–0.72, mean period 1988–2010) above-ground live biomass”, rather than the correct “Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha−1 year−1 (95% CI 0.14–0.72, mean period 1988–2010) in above-ground live biomass carbon”. This has now been corrected in both the PDF and HTML versions of the Article.
Pregnancy and infection: using disease pathogenesis to inform vaccine strategy
Authors: Vermillion Meghan S. , Klein Sabra L.
Published: January 2018

Vaccination is the mainstay of preventative medicine for many infectious diseases. Pregnant women, unborn fetuses, and neonates represent three at-risk populations that can be simultaneously protected by strategic vaccination protocols. Because the pathogenesis of different infectious microbes varies based on tissue tropism, timing of infection, and host susceptibility, the goals of immunization are not uniform across all vaccines. Mechanistic understanding of infectious disease pathogenesis and immune responses is therefore essential to inform vaccine design and the implementation of appropriate immunization protocols that optimize protection of pregnant women, fetuses, and neonates.
Novel insights on new particle formation derived from a pan-european observing system
Authors: Dall’Osto M. , Beddows D. C. S. , Asmi A. , Poulain L. , Hao L. , Freney E. , Allan J. D. , Canagaratna M. , Crippa M. , Bianchi F. , de Leeuw G. , Eriksson A. , Swietlicki E. , Hansson H. C. , Henzing J. S. , Granier C. , Zemankova K. , Laj P. , Onasch T. , Prevot A. , Putaud J. P. , Sellegri K. , Vidal M. , Virtanen A. , Simo R. , Worsnop D. , O’Dowd C. , Kulmala M. , Harrison Roy M.
Published: January 2018

The formation of new atmospheric particles involves an initial step forming stable clusters less than a nanometre in size (<~1 nm), followed by growth into quasi-stable aerosol particles a few nanometres (~1–10 nm) and larger (>~10 nm). Although at times, the same species can be responsible for both processes, it is thought that more generally each step comprises differing chemical contributors. Here, we present a novel analysis of measurements from a unique multi-station ground-based observing system which reveals new insights into continental-scale patterns associated with new particle formation. Statistical cluster analysis of this unique 2-year multi-station dataset comprising size distribution and chemical composition reveals that across Europe, there are different major seasonal trends depending on geographical location, concomitant with diversity in nucleating species while it seems that the growth phase is dominated by organic aerosol formation. The diversity and seasonality of these events requires an advanced observing system to elucidate the key processes and species driving particle formation, along with detecting continental scale changes in aerosol formation into the future.
Characterization of Dopaminergic System in the Striatum of Young Adult Park2−/− Knockout Rats
Authors: Gemechu Jickssa M. , Sharma Akhil , Yu Dongyue , Xie Yuran , Merkel Olivia M. , Moszczynska Anna
Published: January 2018

Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our findings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling.
Plastid phylogenomics with broad taxon sampling further elucidates the distinct evolutionary origins and timing of secondary green plastids
Authors: Jackson Christopher , Knoll Andrew H. , Chan Cheong Xin , Verbruggen Heroen
Published: January 2018

Secondary plastids derived from green algae occur in chlorarachniophytes, photosynthetic euglenophytes, and the dinoflagellate genus Lepidodinium. Recent advances in understanding the origin of these plastids have been made, but analyses suffer from relatively sparse taxon sampling within the green algal groups to which they are related. In this study we aim to derive new insights into the identity of the plastid donors, and when in geological time the independent endosymbiosis events occurred. We use newly sequenced green algal chloroplast genomes from carefully chosen lineages potentially related to chlorarachniophyte and Lepidodinium plastids, combined with recently published chloroplast genomes, to present taxon-rich phylogenetic analyses to further pinpoint plastid origins. We integrate phylogenies with fossil information and relaxed molecular clock analyses. Our results indicate that the chlorarachniophyte plastid may originate from a precusor of siphonous green algae or a closely related lineage, whereas the Lepidodinium plastid originated from a pedinophyte. The euglenophyte plastid putatively originated from a lineage of prasinophytes within the order Pyramimonadales. Our molecular clock analyses narrow in on the likely timing of the secondary endosymbiosis events, suggesting that the event leading to Lepidodinium likely occurred more recently than those leading to the chlorarachniophyte and photosynthetic euglenophyte lineages.
disLocate: tools to rapidly quantify local intermolecular structure to assess two-dimensional order in self-assembled systems
Authors: Bumstead Matt , Liang Kunyu , Hanta Gregory , Hui Lok Shu , Turak Ayse
Published: January 2018

Order classification is particularly important in photonics, optoelectronics, nanotechnology, biology, and biomedicine, as self-assembled and living systems tend to be ordered well but not perfectly. Engineering sets of experimental protocols that can accurately reproduce specific desired patterns can be a challenge when (dis)ordered outcomes look visually similar. Robust comparisons between similar samples, especially with limited data sets, need a finely tuned ensemble of accurate analysis tools. Here we introduce our numerical Mathematica package disLocate, a suite of tools to rapidly quantify the spatial structure of a two-dimensional dispersion of objects. The full range of tools available in disLocate give different insights into the quality and type of order present in a given dispersion, accessing the translational, orientational and entropic order. The utility of this package allows for researchers to extract the variation and confidence range within finite sets of data (single images) using different structure metrics to quantify local variation in disorder. Containing all metrics within one package allows for researchers to easily and rapidly extract many different parameters simultaneously, allowing robust conclusions to be drawn on the order of a given system. Quantifying the experimental trends which produce desired morphologies enables engineering of novel methods to direct self-assembly.
Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities
Authors: Lin Zongtao , Marepally Srinivasa R. , Goh Emily S. Y. , Cheng Chloe Y. S. , Janjetovic Zorica , Kim Tae-Kang , Miller Duane D. , Postlethwaite Arnold E. , Slominski Andrzej T. , Tuckey Robert C. , Peluso-Iltis Carole , Rochel Natacha , Li Wei
Published: January 2018

20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.
Cerebral Perfusion Insufficiency and Relationships with Cognitive Deficits in Alzheimer’s Disease: A Multiparametric Neuroimaging Study
Authors: Huang Chi-Wei , Hsu Shih-Wei , Chang Ya-Ting , Huang Shu-Hua , Huang Yung-Cheng , Lee Chen-Chang , Chang Wen-Neng , Lui Chun-Chung , Chen Na-Ching , Chang Chiung-Chih
Published: January 2018

Micro- or macro-circulatory insufficiency has a negative impact in patients with Alzheimer’s disease (AD). This study used arterial spin-labeled magnetic resonance imaging (ASL-MRI) and ethylcysteinate dimer single-photon emission computed tomography (ECD-SPECT) in 50 patients with AD and 30 age-matched controls to investigate how hypoperfusion patterns were associated with gray matter atrophy and clinical data. All participants completed 3DT1-MRI, ECD-SPECT and ASL-MRI examinations. Medial temporal cortex (MTC) volumes were correlated with regional signals showing significantly lower relative cerebral blood flow (rCBF) in ASL-MRI or perfusion index (PI) in ECD-SPECT. Neurobehavioral scores served as the outcome measures. Regions with lower PI showed spatial similarities with atrophy in the medial, anterior and superior temporal lobes, posterior cingulate cortex and angular gyrus, while regions showing lower rCBF were localized to the distal branches of posterior cerebral artery territories (posterior parietal and inferior temporal lobe) and watershed areas (angular gyrus, precuneus, posterior cingulate gyrus and middle frontal cortex). rCBF values in watershed areas correlated with MTC volumes and language composite scores. Precuneus and angular gyrus hypoperfusion were associated with the corresponding cortical atrophy. Macro- or micro-vasculature perfusion integrities and cortical atrophy determined the overall perfusion imaging topography and contributed differently to the clinical outcomes.
Young and healthy C57BL/6 J mice performing sprint interval training reveal gender- and site-specific changes to the cortical bone
Authors: Hollinski Robin , Osterberg Anja , Polei Stefan , Lindner Tobias , Cantré Daniel , Mittlmeier Thomas , Vollmar Brigitte , Bruhn Sven , Müller-Hilke Brigitte
Published: January 2018

Physical exercise is considered to impede the bone loss associated with physiological ageing however, a training program that efficiently leads to bone accrual in the healthy does not yet exist. We turned to the C57BL/6 J mouse and designed a sprint interval training for treadmill that was tailored to the individual performance limits. It consisted of four weeks with five training sessions each, followed by another four weeks with three. After completion of the training period, mice were sacrificed and the hind legs were analyzed via µCT and MRI for changes in bone parameters and muscle volume, respectively. Increased performance limits in both sexes confirmed an effect of the treadmill training. However, while male tibiae after eight weeks revealed a significant reduction of cortical bone mass at the distal metaphysis, the cross sectional analysis of female tibiae showed a transient decrease of cortical bone mass after four weeks that was reversed into a significant accrual after eight weeks of training and occurred over the entire length of the tibia. The observed net reduction of female bone mass after four weeks of training is suggestive of a remodelling process which may be delayed in the males.
A new dry eye mouse model produced by exorbital and intraorbital lacrimal gland excision
Authors: Shinomiya Katsuhiko , Ueta Mayumi , Kinoshita Shigeru
Published: January 2018

Chronic dry eye is an increasingly prevalent condition worldwide, with resulting loss of visual function and quality of life. Relevant, repeatable, and stable animal models of dry eye are still needed. We have developed an improved surgical mouse model for dry eye based on severe aqueous fluid deficiency, by excising both the exorbital and intraorbital lacrimal glands (ELG and ILG, respectively) of mice. After ELG plus ILG excision, dry eye symptoms were evaluated using fluorescein infiltration observation, tear production measurement, and histological evaluation of ocular surface. Tear production in the model mice was significantly decreased compared with the controls. The corneal fluorescein infiltration score of the model mice was also significantly increased compared with the controls. Histological examination revealed significant severe inflammatory changes in the cornea, conjunctiva or meibomian glands of the model mice after surgery. In the observation of LysM-eGFP(+/−) mice tissues, postsurgical infiltration of green fluorescent neutrophils was observed in the ocular surface tissues. We theorize that the inflammatory changes on the ocular surface of this model were induced secondarily by persistent severe tear reduction. The mouse model will be useful for investigations of both pathophysiology as well as new therapies for tear-volume-reduction type dry eye.
Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer
Authors: Gao Bo , Lu Yi , Nieuweboer Annemieke J. M. , Xu Hongmei , Beesley Jonathan , Boere Ingrid , de Graan Anne-Joy M. , de Bruijn Peter , Gurney Howard , J. Kennedy Catherine , Chiew Yoke-Eng , Johnatty Sharon E. , Beale Philip , Harrison Michelle , Luccarini Craig , Conroy Don , Mathijssen Ron H. J. , R. Harnett Paul , Balleine Rosemary L. , Chenevix-Trench Georgia , Macgregor Stuart , de Fazio Anna
Published: January 2018

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10−5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10−9, empirical P = 1.3 × 10−7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.
Genome-wide association mapping and genomic prediction for CBSD resistance in Manihot esculenta
Authors: Kayondo Siraj Ismail , Pino Del Carpio Dunia , Lozano Roberto , Ozimati Alfred , Wolfe Marnin , Baguma Yona , Gracen Vernon , Offei Samuel , Ferguson Morag , Kawuki Robert , Jannink Jean-Luc
Published: January 2018

Cassava (Manihot esculenta Crantz) is an important security crop that faces severe yield loses due to cassava brown streak disease (CBSD). Motivated by the slow progress of conventional breeding, genetic improvement of cassava is undergoing rapid change due to the implementation of quantitative trait loci mapping, Genome-wide association mapping (GWAS), and genomic selection (GS). In this study, two breeding panels were genotyped for SNP markers using genotyping by sequencing and phenotyped for foliar and CBSD root symptoms at five locations in Uganda. Our GWAS study found two regions associated to CBSD, one on chromosome 4 which co-localizes with a Manihot glaziovii introgression segment and one on chromosome 11, which contains a cluster of nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes. We evaluated the potential of GS to improve CBSD resistance by assessing the accuracy of seven prediction models. Predictive accuracy values varied between CBSD foliar severity traits at 3 months after planting (MAP) (0.27–0.32), 6 MAP (0.40–0.42) and root severity (0.31–0.42). For all traits, Random Forest and reproducing kernel Hilbert spaces regression showed the highest predictive accuracies. Our results provide an insight into the genetics of CBSD resistance to guide CBSD marker-assisted breeding and highlight the potential of GS to improve cassava breeding.
9c11tCLA modulates 11t18:1 and 9t18:1 induced inflammations differently in human umbilical vein endothelial cells
Authors: Li Jing , Hu Sheng-Ben , He Yue-Ming , Zhuo Cheng-Fei , Zhou Ruo-Lin , Chen Fang , Li Hong-yan , Deng Ze-Yuan
Published: January 2018

Endothelial inflammation is recognized as the initial stage of a multistep process leading to coronary heart disease (CHD). Recently, the different effects of industrial trans fatty acids (elaidic acid, 9t18:1) and ruminant trans fatty acids (vaccenic acid, 11t18:1) on CHD have been reported in epidemiological and animal studies, however, the mechanism was not fully studied. Therefore, the objective of this study was to explore the underlying mechanism by which 9t18:1 and 11t18:1 affect human umbilical vein endothelial cells (HUVECs) inflammation. We found that 9c11t-CLA modulated the inflammation of HUVECs induced by 9t18:1 and 11t18:1. Fatty acid composition, pro-inflammatory factors, phosphorylation of MAPKs, and the TLR4 level in HUVECs altered by 11t18:1 induction, collectively suggest that the bio-conversion of 11t18:1 to 9c11tCLA might be the cause why 11t18:1 and 9t18:1 have distinct influences on endothelial injuries. It was concluded that it is biosynthesis of 9c11t CLA from11t18:1, and the modulation of TLR4-MAPK pathway by 9c11t CLA, which at least partially account for the slight effect of 11t18:1 on endothelial inflammation.
Inhibition of angiogenesis by leflunomide via targeting the soluble ephrin-A1/EphA2 system in bladder cancer
Authors: Chu Maolin , Zhang Chunying
Published: January 2018

Angiogenesis plays an important role in bladder cancer (BCa). The immunosuppressive drug leflunomide has attracted worldwide attention. However, the effects of leflunomide on angiogenesis in cancer remain unclear. Here, we report the increased expression of soluble ephrin-A1 (sEphrin-A1) in supernatants of BCa cell lines (RT4, T24, and TCCSUP) co-cultured with human umbilical vein endothelial cells (HUVECs) compared with that in immortalized uroepithelial cells (SV-HUC-1) co-cultured with HUVECs. sEphrin-A1 is released from BCa cells as a monomeric protein that is a functional form of the ligand. The co-culture supernatants containing sEphrin-A1 caused the internalization and down-regulation of EphA2 on endothelial cells and dramatic functional activation of HUVECs. This sEphrin-A1/EphA2 system is mainly functional in regulating angiogenesis in BCa tissue. We showed that leflunomide (LEF) inhibited angiogenesis in a N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced bladder carcinogenesis model and a tumor xenograft model, as well as in BCa cell and HUVEC co-culture systems, via significant inhibition of the sEphrin-A1/EphA2 system. Ephrin-A1 overexpression could partially reverse LEF-induced suppression of angiogenesis and subsequent tumor growth inhibition. Thus, LEF has a significant anti-angiogenesis effect on BCa cells and BCa tissue via its inhibition of the functional angiogenic sEphrin-A1/EphA2 system and may have potential for treating BCa beyond immunosuppressive therapy.
Vertical Light Sheet Enhanced Side-View Imaging for AFM Cell Mechanics Studies
Authors: Beicker Kellie , O’Brien E. Timothy , Falvo Michael R. , Superfine Richard
Published: January 2018

The ability to measure dynamic structural changes within a cell under applied load is essential for developing more accurate models of cell mechanics and mechanotransduction. Atomic force microscopy is a powerful tool for evaluating cell mechanics, but the dominant applied forces and sample strains are in the vertical direction, perpendicular to the imaging plane of standard fluorescence imaging. Here we report on a combined sideways imaging and vertical light sheet illumination system integrated with AFM. Our system enables high frame rate, low background imaging of subcellular structural dynamics in the vertical plane synchronized with AFM force data. Using our system for cell compression measurements, we correlated stiffening features in the force indentation data with onset of nuclear deformation revealed in the imaging data. In adhesion studies we were able to correlate detailed features in the force data during adhesive release events with strain at the membrane and within the nucleus.
Effect of spin relaxations on the spin mixing conductances for a bilayer structure
Authors: Li D. X. , Shen H. Z. , Liu H. D. , Yi X. X.
Published: January 2018

The spin current can result in a spin-transfer torque in the normal-metal(NM)—ferromagnetic-insulator(FMI) or normal-metal(NM)—ferromagnetic-metal(FMM) bilayer. In the earlier study on this issue, the spin relaxations were ignored or introduced phenomenologically. In this paper, considering the FMM or FMI with spin relaxations described by a non-Hermitian Hamiltonian, we derive an effective spin-transfer torque and an effective spin mixing conductance in the non-Hermitian bilayer. The dependence of the effective spin mixing conductance on the system parameters (such as insulating gap, s-d coupling, and layer thickness) as well as the relations between the real part and the imaginary part of the effective spin mixing conductance are given and discussed. We find that the effective spin mixing conductance can be enhanced in the non-Hermitian system. This provides us with the possibility to enhance the spin mixing conductance.
Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics
Authors: Jones Anya C. , Troy Niamh M. , White Elisha , Hollams Elysia M. , Gout Alexander M. , Ling Kak-Ming , Kicic Anthony , Stick Stephen M. , Sly Peter D. , Holt Patrick G. , Hall Graham L. , Bosco Anthony
Published: January 2018

Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis. We employed RNA-Seq profiling of sputum-derived cells to identify gene networks operative at baseline in house dust mite-sensitized (HDMS) subjects with/without wheezing history that are characteristic of the ongoing asthmatic state. The expression of type 2 effectors (IL-5, IL-13) was equivalent in both cohorts of subjects. However, in HDMS-wheezers they were associated with upregulation of two coexpression modules comprising multiple type 2- and epithelial-associated genes. The first module was interlinked by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3 and mucociliary clearance genes. Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatics undergoing natural aeroallergen exposure, and suggest that susceptibility to asthma amongst these subjects involves complex interactions between type 2- and epithelial-associated gene networks, which are not operative in equivalently sensitized/exposed atopic non-asthmatics.
The gait speed advantage of taller stature is lost with age
Authors: Elbaz Alexis , Artaud Fanny , Dugravot Aline , Tzourio Christophe , Singh-Manoux Archana
Published: January 2018

Taller individuals walk faster but it is unknown whether this advantage persists at older ages. We examined the cross-sectional/longitudinal associations of height with gait speed (GS) in participants from the Dijon-Three-City cohort study (France) over 11 years. In 4011 participants (65–85 y), we measured usual/fast GS (6 m) up to five times. We examined whether the baseline height-GS association varied with age using linear regression, and whether height influenced GS change using linear mixed models. Taller participants 65 y at baseline walked faster than shorter ones (fast GS difference between top/bottom height quartiles, 0.100 m/s, P < 0.001); this association weakened with age (P-interaction = 0.02), with a 0.012 m/s (P = 0.57) difference at 80 y. Ten-year fast GS decline was 51% greater (P < 0.001) in younger participants in the top height quartile (−0.183 m/s) compared to those in the bottom quartile (−0.121 m/s), leading the GS difference between the two groups to be attenuated by 50% over the follow-up. The height-related difference in fast GS decline was not explained by time-dependent comorbidities or height shrinkage. Analyses for usual GS yielded consistent findings. The height-GS relation is more complex than previously thought, as the height related advantage in GS disappears as persons grow older due to faster decline in taller compared to shorter persons.
Integrating transient cellular and nuclear motions to comprehensively describe cell migration patterns
Authors: Lan Tian , Hung Shen-Hsiu , Su Xudong , Wong Samuel W. K. , Tseng Yiider
Published: January 2018

Various subcellular activities, such as protrusion and detachment, compose a cell migration process. The molecular mechanisms of these subcellular activities have been elucidated. However, there is no method that can assess the contributions of these subcellular activities to the global cell migration pattern of a given cell type. Hence, we develop a powerful approach based on CN correlations that quantitatively profiles the cell migration pattern of a given cell type in terms of assembled subcellular activities. In this way, we bridge migration data at the cellular level with underlying molecular mechanisms. The CN correlation profile is found to uniquely and consistently represent the cell migration pattern of each cell type probed. It can clearly reveal the effects of molecular perturbations, such as Y27632 and Cdc42 knockdown on each subcellular migratory activity. As a result, the CN correlation approach serves as a cell dynamic descriptor that can extract comprehensive quantitative data from cell migration movies for integrative biological analyses.
Active microbial biofilms in deep poor porous continental subsurface rocks
Authors: Escudero Cristina , Vera Mario , Oggerin Monike , Amils Ricardo
Published: January 2018

Deep continental subsurface is defined as oligotrophic environments where microorganisms present a very low metabolic rate. To date, due to the energetic cost of production and maintenance of biofilms, their existence has not been considered in poor porous subsurface rocks. We applied fluorescence in situ hybridization techniques and confocal laser scanning microscopy in samples from a continental deep drilling project to analyze the prokaryotic diversity and distribution and the possible existence of biofilms. Our results show the existence of natural microbial biofilms at all checked depths of the Iberian Pyrite Belt (IPB) subsurface and the co-occurrence of bacteria and archaea in this environment. This observation suggests that multi-species biofilms may be a common and widespread lifestyle in subsurface environments.
Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition
Authors: Rai Yogesh , Pathak Richa , Kumari Neeraj , Sah Dhananjay Kumar , Pandey Sanjay , Kalra Namita , Soni Ravi , Dwarakanath B. S. , Bhatt Anant Narayan
Published: January 2018

Metabolic viability based high throughput assays like MTT and MTS are widely used in assessing the cell viability. However, alteration in both mitochondrial content and metabolism can influence the metabolic viability of cells and radiation is a potential mitochondrial biogenesis inducer. Therefore, we tested if MTT assay is a true measure of radiation induced cell death in widely used cell lines. Radiation induced cellular growth inhibition was performed by enumerating cell numbers and metabolic viability using MTT assay at 24 and 48 hours (hrs) after exposure. The extent of radiation induced reduction in cell number was found to be larger than the decrease in MTT reduction in all the cell lines tested. We demonstrated that radiation induces PGC-1α and TFAM to stimulate mitochondrial biogenesis leading to increased levels of SDH-A and enhanced metabolic viability. Radiation induced disturbance in calcium (Ca2+) homeostasis also plays a crucial role by making the mitochondria hyperactive. These findings suggest that radiation induces mitochondrial biogenesis and hyperactivation leading to increased metabolic viability and MTT reduction. Therefore, conclusions drawn on radiation induced growth inhibition based on metabolic viability assays are likely to be erroneous as it may not correlate with growth inhibition and/or loss of clonogenic survival.
New 2-Aryl-9-methyl-β-carbolinium salts as Potential Acetylcholinesterase Inhibitor agents: Synthesis, Bioactivity and Structure–Activity Relationship
Authors: Zhou Bohang , Zhang Bingyu , Li Xingqiang , Liu Xiuxiu , Li Hui , Li Ding , Cui Zhiming , Geng Huiling , Zhou Le
Published: January 2018

A series of 2-aryl-9-methyl-β-carbolinium bromides (B) were synthesized and explored for anti-acetylcholinesterase (AChE) activities in vitro, action mechanism and structure-activity relationship. All the compounds B along with their respective 3,4-dihydro intermediates (A) presented anti-AChE activity at 10 μM. Thirteen compounds B showed the excellent activity with IC50 values of 0.11–0.76 μM and high selectivity toward AChE relative to butyrylcholinesterase (BChE), superior to galantamine (IC50 = 0.79 μM), a selective AChE inhibitor drug. Kinetic analysis showed that the action mechanisms of both compounds B and A are a competitive inhibition model. Structure-activity relationship analyses showed that the C = N+ moiety is a determinant for the activity. Substituents at 6, 7 or 4′ site, the indole-N-alkyl and the aromatization of the C-ring can significantly improve the activity. Molecular docking studies showed that the compounds could combine with the active site of AChE by the π-π or cation-π action between the carboline ring and the phenyl rings of the residues, and the β-carboline moiety is embedded in a cavity surrounded by four aromatic residues of Trp86, Tyr337, Trp439 and Tyr449. The present results strongly suggest that the para-position of the D-ring should be a preferred modification site for further structural optimization design. Thus, 2-aryl-9-methyl-β-carboliniums emerged as novel and promising tool compounds for the development of new AChE inhibitor agents.
Antimicrobial activity of Ti-ZrN/Ag coatings for use in biomaterial applications
Authors: Slate Anthony J. , Wickens David J. , El Mohtadi Mohamed , Dempsey-Hibbert Nina , West Glen , Banks Craig E. , Whitehead Kathryn A.
Published: January 2018

Severely broken bones often require external bone fixation pins to provide support but they can become infected. In order to reduce such infections, novel solutions are required. Titanium zirconium nitride (Ti-ZrN) and Ti-ZrN silver (Ti-ZrN/Ag) coatings were deposited onto stainless steel. Surface microtopography demonstrated that on the silver containing surfaces, S
a
and S
v
values demonstrated similar trends whilst the R
a
, average height and RMS value and S
p
values increased with increasing silver concentration. On the Ti-ZrN/Ag coatings, surface hydrophobicity followed the same trend as the S
a
and S
v
values. An increase in dead Staphylococcus aureus and Staphylococcus epidermidis cells was observed on the coatings with a higher silver concentration. Using CTC staining, a significant increase in S. aureus respiration on the silver containing surfaces was observed in comparison to the stainless steel control whilst against S. epidermidis, no significant difference in viable cells was observed across the surfaces. Cytotoxicity testing revealed that the TiZrN coatings, both with and without varying silver concentrations, did not possess a detrimental effect to a human monocyte cell line U937. This work demonstrated that such coatings have the potential to reduce the viability of bacteria that result in pin tract infections.
Use of whole genome sequencing to investigate an increase in Neisseria gonorrhoeae infection among women in urban areas of Australia
Authors: Buckley Cameron , Forde Brian M. , Trembizki Ella , Lahra Monica M. , Beatson Scott A. , Whiley David M.
Published: January 2018

Increasing rates of gonorrhoea have been observed among women within the Australian state of New South Wales. Here, we applied whole genome sequencing (WGS) to better understand the associated networks and transmission dynamics. Ninety-four isolates of a particular N. gonorrhoeae genotype (G122) associated with women (years 2012 to 2014) underwent phylogenetic analysis using core single nucleotide polymorphisms. WGS data revealed five main clusters, all of which were heterogeneous in terms of patient age and site of infection. The relatively high cervical/vaginal infections in each cluster was indicative of transmission in the general heterosexual population, noting that there is typically high rates of condom use for vaginal sex among local commercial sex workers. WGS also enabled the identification of groups of individuals belonging to tighter transmission chains within clusters, and hence may present a new tool for targeting public health interventions. The enhanced resolution of WGS provides a ready means of confirming suspected changes in N. gonorrhoeae epidemiology, but also enables key features to be identified or new questions to be raised regarding the composition of the associated sexual networks.
Graphene-based nonvolatile terahertz switch with asymmetric electrodes
Authors: Li Yan , Yu Hui , Qiu Xinyu , Dai Tingge , Jiang Jianfei , Wang Gencheng , Zhang Qiang , Qin Yali , Yang Jianyi , Jiang Xiaoqing
Published: January 2018

We propose a nonvolatile terahertz (THz) switch which is able to perform the switching with transient stimulus. The device utilizes graphene as its floating-gate layer, which changes the transmissivity of THz signal by trapping the tunneling charges. The conventional top-down electrode configuration is replaced by a left-right electrode configuration, so THz signals could transmit through this device with the transmissivity being controlled by voltage pulses. The two electrodes are made of metals with different work functions. The resultant asymmetrical energy band structure ensures that both electrical programming and erasing are viable. With the aid of localized surface plasmon resonances in graphene ribbon arrays, the modulation depth is 89% provided that the Femi level of graphene is tuned between 0 and 0.2 eV by proper voltage pulses.
High diversity and abundance of cultivable tetracycline-resistant bacteria in soil following pig manure application
Authors: Kang Yijun , Li Qing , Yin Zhifeng , Shen Min , Zhao Haitao , Bai Yanchao , Mei Lijuan , Hu Jian
Published: January 2018

By performing a microcosm experiment mimicking fertilization, we assessed the dynamic distribution of tetracycline-resistant bacteria (TRB) and corresponding tetracycline resistance genes (TRGs) from pig manure (PM) to the fertilized soil, by culture-dependent methods and PCR detection. Cultivable TRB were most abundant in PM, followed by fertilized soil and unfertilized soil. By restriction fragment length polymorphism (RFLP) analysis, TRB were assigned to 29, 20, and 153 operational taxonomic units (OTUs) in PM, unfertilized soil, and fertilized soil, respectively. After identification, they were further grouped into 19, 12, and 62 species, showing an enhanced diversity of cultivable TRB in the soil following PM application. The proportions of potentially pathogenic TRB in fertilized soil decreased by 69.35% and 41.92% compared with PM and unfertilized soil. Bacillus cereus was likely widely distributed TRB under various environments, and Rhodococcus erythropolis and Acinetobacter sp. probably spread from PM to the soil via fertilization. Meanwhile, tetL was the most common efflux pump gene in both unfertilized and fertilized soils relative to PM; tetB(P) and tet36 were common in PM, whereas tetO was predominant in unfertilized and fertilized soil samples. Sequencing indicated that over 65% of randomly selected TRB in fertilized soil with acquired resistance derived from PM.