bluuebunny/crossref_metadata_2025 huggingface dataset:
Arkadia/RNF111 is a SUMO-targeted ubiquitin ligase with preference for substrates marked with SUMO1-capped SUMO2/3 chain
Authors: Sriramachandran Annie M. , Meyer-Teschendorf Katrin , Pabst Stefan , Ulrich Helle D. , Gehring Niels H. , Hofmann Kay , Praefcke Gerrit J. K. , Dohmen R. Jürgen
Published: August 2019

Modification with SUMO regulates many eukaryotic proteins. Down-regulation of sumoylated forms of proteins involves either their desumoylation, and hence recycling of the unmodified form, or their proteolytic targeting by ubiquitin ligases that recognize their SUMO modification (termed STUbL or ULS). STUbL enzymes such as Uls1 and Slx5-Slx8 in budding yeast or RNF4 and Arkadia/RNF111 in humans bear multiple SUMO interaction motifs to recognize substrates carrying poly-SUMO chains. Using yeast as experimental system and isothermal titration calorimetry, we here show that Arkadia specifically selects substrates carrying SUMO1-capped SUMO2/3 hybrid conjugates and targets them for proteasomal degradation. Our data suggest that a SUMO1-specific binding site in Arkadia with sequence similarity to a SUMO1-binding site in DPP9 is required for targeting endogenous hybrid SUMO conjugates and PML nuclear bodies in human cells. We thus characterize Arkadia as a STUbL with a preference for substrate proteins marked with distinct hybrid SUMO chains.
Publisher Correction: ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
Authors: Cao Yu , Trillo-Tinoco Jimena , Sierra Rosa A. , Anadon Carmen , Dai Wenjie , Mohamed Eslam , Cen Ling , Costich Tara L. , Magliocco Anthony , Marchion Douglas , Klar Richard , Michel Sven , Jaschinski Frank , Reich Richard R. , Mehrotra Shikhar , Cubillos-Ruiz Juan R. , Munn David H. , Conejo-Garcia Jose R. , Rodriguez Paulo C.
Published: August 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese
Authors: Kou Ikuyo , Otomo Nao , Takeda Kazuki , Momozawa Yukihide , Lu Hsing-Fang , Kubo Michiaki , Kamatani Yoichiro , Ogura Yoji , Takahashi Yohei , Nakajima Masahiro , Minami Shohei , Uno Koki , Kawakami Noriaki , Ito Manabu , Yonezawa Ikuho , Watanabe Kei , Kaito Takashi , Yanagida Haruhisa , Taneichi Hiroshi , Harimaya Katsumi , Taniguchi Yuki , Shigematsu Hideki , Iida Takahiro , Demura Satoru , Sugawara Ryo , Fujita Nobuyuki , Yagi Mitsuru , Okada Eijiro , Hosogane Naobumi , Kono Katsuki , Nakamura Masaya , Chiba Kazuhiro , Kotani Toshiaki , Sakuma Tsuyoshi , Akazawa Tsutomu , Suzuki Teppei , Nishida Kotaro , Kakutani Kenichiro , Tsuji Taichi , Sudo Hideki , Iwata Akira , Sato Tatsuya , Inami Satoshi , Matsumoto Morio , Terao Chikashi , Watanabe Kota , Ikegawa Shiro
Published: August 2019

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.
Global subsoil organic carbon turnover times dominantly controlled by soil properties rather than climate
Authors: Luo Zhongkui , Wang Guocheng , Wang Enli
Published: August 2019

Soil organic carbon (SOC) in the subsoil below 0.3 m accounts for the majority of total SOC and may be as sensitive to climate change as topsoil SOC. Here we map global SOC turnover times (τ) in the subsoil layer at 1 km resolution using observational databases. Global mean τ is estimated to be $$1015_{729}^{1414}$$
101

5

729

1414

yr (mean with 95% confidence interval), and deserts and tundra show the shortest ($$146_{114}^{188}$$
14

6

114

188

yr) and longest ($$3854_{2651}^{5622}$$
385

4

2651

5622

yr) τ respectively. Across the globe, mean τ ranges from 9 (the 5% quantile) to 6332 years (the 95% quantile). Temperature is the most important factor negatively affecting τ, but the overall effect of climate (including temperature and precipitation) is secondary compared with the overall effect of assessed soil properties (e.g., soil texture and pH). The high-resolution mapping of τ and the quantification of its controls provide a benchmark for diagnosing subsoil SOC dynamics under climate change.
Stiffening of graphene oxide films by soft porous sheets
Authors: Mao Lily , Park Hun , Soler-Crespo Rafael A. , Espinosa Horacio D. , Han Tae Hee , Nguyen SonBinh T. , Huang Jiaxing
Published: August 2019

Graphene oxide (GO) sheets have been used as a model system to study how the mechanical properties of two-dimensional building blocks scale to their bulk form, such as paper-like, lamellar-structured thin films. Here, we report that the modulus of multilayer GO films can be significantly enhanced if some of the sheets are drastically weakened by introducing in-plane porosity. Nanometer-sized pores are introduced in GO sheets by chemical etching. Membrane-deflection measurements at the single-layer level show that the sheets are drastically weakened as the in-plane porosity increases. However, the mechanical properties of the corresponding multilayer films are much less sensitive to porosity. Surprisingly, the co-assembly of pristine and etched GO sheets yields even stiffer films than those made from pristine sheets alone. This is attributed to the more compliant nature of the soft porous sheets, which act as a binder to improve interlayer packing and load transfer in the multilayer films.
Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
Authors: Vedanayagam Jeffrey , Chatila Walid K. , Aksoy Bülent Arman , Majumdar Sonali , Skanderup Anders Jacobsen , Demir Emek , Schultz Nikolaus , Sander Chris , Lai Eric C.
Published: August 2019

Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms. Here, we characterize an unstudied, recurrent, mutation (S1344L) in the DICER1 RNase IIIa domain in tumors from The Cancer Genome Atlas (TCGA) project and MSK-IMPACT profiling. RNase IIIa/b hotspots are absent from most cancers, but are notably enriched in uterine cancers. Systematic analysis of TCGA small RNA datasets show that DICER1 RNase IIIa-S1344L tumors deplete 5p-miRNAs, analogous to RNase IIIb hotspot samples. Structural and evolutionary coupling analyses reveal constrained proximity of RNase IIIa-S1344 to the RNase IIIb catalytic site, rationalizing why mutation of this site phenocopies known hotspot alterations. Finally, examination of DICER1 hotspot endometrial tumors reveals derepression of specific miRNA target signatures. In summary, comprehensive analyses of DICER1 somatic mutations and small RNA data reveal a mechanistic aspect of pre-miRNA processing that manifests in specific cancer settings.
Interplay of protein corona and immune cells controls blood residency of liposomes
Authors: Giulimondi Francesca , Digiacomo Luca , Pozzi Daniela , Palchetti Sara , Vulpis Elisabetta , Capriotti Anna Laura , Chiozzi Riccardo Zenezini , Laganà Aldo , Amenitsch Heinz , Masuelli Laura , Peruzzi Giovanna , Mahmoudi Morteza , Screpanti Isabella , Zingoni Alessandra , Caracciolo Giulio
Published: August 2019

In vivo liposomes, like other types of nanoparticles, acquire a totally new ‘biological identity’ due to the formation of a biomolecular coating known as the protein corona that depends on and modifies the liposomes’ synthetic identity. The liposome–protein corona is a dynamic interface that regulates the interaction of liposomes with the physiological environment. Here we show that the biological identity of liposomes is clearly linked to their sequestration from peripheral blood mononuclear cells (PBMCs) of healthy donors that ultimately leads to removal from the bloodstream. Pre-coating liposomes with an artificial corona made of human plasma proteins drastically reduces capture by circulating leukocytes in whole blood and may be an effective strategy to enable prolonged circulation in vivo. We conclude with a critical assessment of the key concepts of liposome technology that need to be reviewed for its definitive clinical translation.
Molecular mass growth through ring expansion in polycyclic aromatic hydrocarbons via radical–radical reactions
Authors: Zhao Long , Kaiser Ralf. I. , Lu Wenchao , Xu Bo , Ahmed Musahid , Morozov Alexander N. , Mebel Alexander M. , Howlader A. Hasan , Wnuk Stanislaw F.
Published: August 2019

Polycyclic aromatic hydrocarbons (PAHs) represent key molecular building blocks leading to carbonaceous nanoparticles identified in combustion systems and extraterrestrial environments. However, the understanding of their formation and growth in these high temperature environments has remained elusive. We present a mechanism through laboratory experiments and computations revealing how the prototype PAH—naphthalene—can be efficiently formed via a rapid 1-indenyl radical—methyl radical reaction. This versatile route converts five- to six-membered rings and provides a detailed view of high temperature mass growth processes that can eventually lead to graphene-type PAHs and two-dimensional nanostructures providing a radical new view about the transformations of carbon in our universe.
Author Correction: SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis
Authors: Zhou Huanjiao Jenny , Xu Zhe , Wang Zongren , Zhang Haifeng , Zhuang Zhen W. , Simons Michael , Min Wang
Published: August 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Evidence of conditioned behavior in amoebae
Authors: De la Fuente Ildefonso M. , Bringas Carlos , Malaina Iker , Fedetz María , Carrasco-Pujante Jose , Morales Miguel , Knafo Shira , Martínez Luis , Pérez-Samartín Alberto , López José I. , Pérez-Yarza Gorka , Boyano María Dolores
Published: August 2019

Associative memory is the main type of learning by which complex organisms endowed with evolved nervous systems respond efficiently to certain environmental stimuli. It has been found in different multicellular species, from cephalopods to humans, but never in individual cells. Here we describe a motility pattern consistent with associative conditioned behavior in the microorganismAmoeba proteus. We use a controlled direct-current electric field as the conditioned stimulus, and a specific chemotactic peptide as the unconditioned stimulus. The amoebae are capable of linking two independent past events, generating persistent locomotion movements that can prevail for 44 min on average. We confirm a similar behavior in a related species,Metamoeba leningradensis. Thus, our results indicate that unicellular organisms can modify their behavior during migration by associative conditioning.
Pseudomonas aeruginosa Induced Host Epithelial Cell Mitochondrial Dysfunction
Authors: Maurice Nicholas M. , Bedi Brahmchetna , Yuan Zhihong , Goldberg Joanna B. , Koval Michael , Hart C. Michael , Sadikot Ruxana T.
Published: August 2019

The pathogenicity of P. aeruginosa is dependent on quorum sensing (QS), an inter-bacterial communication system that can also modulate host biology. The innate immune function of the lung mucosal barrier is dependent on proper mitochondrial function. The purpose of this study was to define the mechanism by which bacterial factors modulate host lung epithelial cell mitochondrial function and to investigate novel therapies that ameliorate this effect. 3-oxo-C12-HSL disrupts mitochondrial morphology, attenuates mitochondrial bioenergetics, and induces mitochondrial DNA oxidative injury. Mechanistically, we show that 3-oxo-C12-HSL attenuates expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration, and its downstream effectors in both BEAS-2B and primary lung epithelial cells. Overexpression of PGC-1α attenuates the inhibition in cellular respiration caused by 3-oxo-C12-HSL. Pharmacologic activation of PGC-1α restores barrier integrity in cells treated with 3-oxo-C12-HSL. These data demonstrate that the P. aeruginosa QS molecule, 3-oxo-C12-HSL, alters mitochondrial pathways critical for lung mucosal immunity. Genetic and pharmacologic strategies that activate the PGC-1α pathway enhance host epithelial cell mitochondrial function and improve the epithelial innate response to P. aeruginosa. Therapies that rescue PGC-1α function may provide a complementary approach in the treatment of P. aeruginosa infection.
Donepezil modulates amyloid precursor protein endocytosis and reduction by up-regulation of SNX33 expression in primary cortical neurons
Authors: Takada-Takatori Yuki , Nakagawa Shota , Kimata Riko , Nao Yousuke , Mizukawa Yumiko , Urushidani Tetsuro , Izumi Yasuhiko , Akaike Akinori , Tsuchida Katsuharu , Kume Toshiaki
Published: August 2019

Donepezil, a therapeutic drug for Alzheimer’s disease, ameliorates cognitive dysfunction through selective inhibition of acetylcholinesterase. However, recent studies have also reported off-target effects of donepezil that likely contribute to its therapeutic effects. In this study, we investigated the (i) role of donepezil in amyloid precursor protein (APP) processing and (ii) involvement of sorting nexin protein 33 (SNX33), a member of the sorting nexin protein family, in this processing. Results showed that donepezil induces an increase in SNX33 expression in primary cortical neurons. The secretion of sAPPα in culture media increased, whereas the expression of full-length APP in the cell lysate remained unchanged. Exposure of cortical cultures to donepezil led to a decrease in amyloid β (Aβ) protein levels in a concentration- and time-dependent manner. This decrease was not affected by concomitant treatment with acetylcholine receptor antagonists. SNX33 knockdown by target-specific morpholino oligos inhibited the effects of donepezil. Donepezil treatment increased cell membrane surface expression of APP in SNX33 expression-dependent manner. These results suggested that donepezil decreases the level of Aβ by increasing SNX33 expression and APP cleavage by α-secretase in cortical neurons.
A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis
Authors: Rosenthal Sara Brin , Bush Kevin T. , Nigam Sanjay K.
Published: August 2019

Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network—including SLC and ABC “drug” transporters, “drug” metabolizing enzymes (DMEs), and regulatory genes—is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4α, HNF1α, and PXR. Knockout gene expression data confirmed ~60–70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney “remote sensing and signaling network” consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules.
Publisher Correction: Five-month-old infants detect affiliation in colaughter
Authors: Vouloumanos Athena , Bryant Gregory A.
Published: August 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia
Authors: Yoon Jae-Ho , Kim Hee-Je , Min Gi June , Park Sung-Soo , Jeon Young-Woo , Lee Sung-Eun , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Lee Seok , Min Chang-Ki , Cho Seok-Goo , Lee Jong Wook
Published: August 2019

Acute promyelocytic leukemia (APL) is generally held to have favorable risk, but we have observed a high incidence of early deaths caused by fatal bleeding and differentiation syndrome (DS). We retrospectively analyzed 259 APL patients from 2002 to 2014 who all received all-trans retinoic acid (ATRA) with the support of sufficient transfusions, followed by 4 days of idarubicin. High-risk status was determined as a diagnostic leukocyte count (WBCdx) >10 × 109/L (Sanz criteria). For patients with hyperleukocytosis, we sometimes conducted leukapheresis and also used hydroxyurea and prophylactic dexamethasone. Because we frequently observed patient fatalities from progressive hyperleukocytosis, we also checked the maximum leukocyte count (WBCmax) and stratified patients by their incremental ratios. The 8-week cumulative incidence of early death and DS was 13.5% and 17.8%, respectively. We found that WBCmax correlated better with early death and DS, even in the low-risk group, than WBCdx. Among the patients with WBCdx <10 × 109/L, a WBCmax >43 × 109/L correlated with early death (26.7%) and DS (40.0%). Also, having a WBCdx of 10 to 43 × 109/La that increased to a WBCmax >43 × 109/L correlated with increased early death (33.3%). The multivariate analysis revealed that a WBCmax >43 × 109/L correlated significantly with both early death and DS.
Molecular profiling and antimicrobial resistance of Shiga toxin-producing Escherichia coli O26, O45, O103, O121, O145 and O157 isolates from cattle on cow-calf operations in South Africa
Authors: Karama Musafiri , Mainga Alfred O. , Cenci-Goga Beniamino T. , Malahlela Mogaugedi , El-Ashram Saeed , Kalake Alan
Published: August 2019

In this study, 140 cattle STEC isolates belonging to serogroups O157, O26, O145, O121, O103 and O45 were characterized for 38 virulence-associated genes, antimicrobial resistance profiles and genotyped by PFGE. The majority of isolates carried both stx1 and stx2 concurrently, stx2c, and stx2d; plasmid-encoded genes ehxA, espP, subA and saa but lacked katP and etpD and eaeA. Possession of eaeA was significantly associated with the presence of nle genes, katP, etpD, ureC and terC. However, saa and subA, stx1c and stx1d were only detected in eaeA negative isolates. A complete OI-122 and most non-LEE effector genes were detected in only two eaeA positive serotypes, including STEC O157:H7 and O103:H2. The eaeA gene was detected in STEC serotypes that are commonly implicated in severe humans disease and outbreaks including STEC O157:H7, STEC O145:H28 and O103:H2. PFGE revealed that the isolates were highly diverse with very low rates of antimicrobial resistance. In conclusion, only a small number of cattle STEC serotypes that possessed eaeA, had the highest number of virulence-associated genes, indicative of their high virulence. Further characterization of STEC O157:H7, STEC O145:H28 and O103:H2 using whole genome sequencing will be needed to fully understand their virulence potential for humans.
Development of anchialine cave habitats and karst subterranean estuaries since the last ice age
Authors: van Hengstum Peter J. , Cresswell Jacque N. , Milne Glenn A. , Iliffe Thomas M.
Published: August 2019

Extinction models generally predict that coastal and neritic fauna benefit during sea-level rise (transgression), whereas sea-level retreat (regression) diminishes their suitable habitat area and promotes evolutionary bottlenecks. Sea-level change also impacts terrestrial island biogeography, but it remains a challenge to evidence how sea-level rise impacts aquatic island biogeography, especially in the subterranean realm. Karst subterranean estuaries (KSEs) occur globally on carbonate islands and platforms, and they are populated by globally-dispersed, ancient ecosystems (termed anchialine). Anchialine fauna currently exhibit a disjunct biogeography that cannot be completely explained by plate tectonic-imposed vicariance. Here we provide evidence that anchialine ecosystems can experience evolutionary bottlenecks caused by habitat reduction during transgression events. Marine-adapted anchialine fauna benefit from habitat expansion during transgressions, but fresh- and brackish-adapted fauna must emigrate, evolve to accommodate local habitat changes, or are regionally eliminated. Phanerozoic transgressions relative to long-term changes in subsidence and relief of regional lithology must be considered for explaining biogeography, evolution, local extirpation or complete extinction of anchialine fauna. Despite the omission of this entire category of environments and animals in climate change risk assessments, the results indicate that anchialine fauna on low-lying islands and platforms that depend upon meteoric groundwater are vulnerable to habitat changes caused by 21st century sea-level rise.
Wavelength-adaptable effective q-plates with passively tunable retardance
Authors: B Radhakrishna , Kadiri Gururaj , Raghavan G
Published: August 2019

Wave retarders having spatially varying optical axes orientations, called q-plates are extremely efficient devices for converting spin to orbital angular momentum of light and for the generation of optical vortices. Most often, these plates are designed for a specific wavelength and have a homogeneous constant retardance. The present work provides a polarimetric approach for overcoming both these limitations. We theoretically propose and experimentally demonstrate q-plates with tunable retardance, employing a combination of only standard q-plates and waveplates. A clear prescription is provided for realizing wavelength indepedent q-plates for a desired retardance, with a potential for ultrafast switching. Apart from the potential commercial value of the proposed devices, our results may find applications in quantum communication protocols, astronomical coronography, angular momentum sorting and in schemes that leverage optical vortices and spin to orbital angular momentum conversion.
AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks
Authors: Yamada Shintaro , Kamata Taito , Nawa Hiroyuki , Sekijima Tsuneo , Takei Nobuyuki
Published: August 2019

During hibernation, mammalian cells are exposed to severe environmental stressors such as low temperature, lowered O2 supply, and glucose deficiency. The cellular metabolic rate is markedly reduced for adapting to these conditions. AMP-activated protein kinase (AMPK) senses the cellular energy status and regulates metabolism. Therefore, we examined AMPK signaling in several brain regions and peripheral tissues in hibernating chipmunk. Eukaryotic elongation factor 2 (eEF2) is a downstream target of AMPK. Phosphorylation of eEF2, indicating its inactivation, is enhanced in the cerebral cortex of hibernating chipmunks. The study indicated that the sequential regulation of AMPK-mammalian target of rapamycin complex 1-eEF2 signaling was altered and protein synthesis ability was reduced in the cerebral cortex of hibernating chipmunks.
Prevalence and outcome of invasive pulmonary aspergillosis in critically ill patients with liver cirrhosis: an observational study
Authors: Lahmer Tobias , Brandl Andreas , Rasch Sebastian , Baires Gonzalo Batres , Schmid Roland M. , Huber Wolfgang , Mayr Ulrich
Published: August 2019

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity/mortality in critically ill patients with endstage liver disease. Therefore, aim of this study is to predict the prevalence and outcome of IPA in critically ill patients with underlying liver cirrhosis and evaluation of the necessity Glactomannan (GM) screening in serum and bronchoalveolar lavage (BAL) in this cohort. In total 12 out of 84 patients (14%) had probable IPA. The mean optical density index (ODI) bronchoalveolar lavage (BAL) GM index was 3.6 ± 1.5 (Range: 1.7–5.7). An overall sensitivity of 90% (95% CI 86–96%) and specificity of 85% (95% CI 81–88%) was found for the BAL GM in IPA. Acute Physiology And Chronic Health Evaluation (APACHE II), sequential organ failure assessment (SOFA) as well the model of endstage liver disease (MELD) score were significantly higher in the probable IPA group as compared to the No IPA group (26 versus 21, p < 0.001 and 14 versus 10, p < 0.044). Length of intensive care unit (ICU) stay was significantly longer in probable IPA patients (16 versus 10 days, p < 0.027) and mortality rate was significantly higher in probable IPA patients (100% versus 65%, p < 0.001) as compared to No IPA patients. APACHE II and MELD score were independently associated with higher mortality rate using multivariate logistic regression (p = 0.025 and p = 0.034). In conclusion, IPA has a relevant impact on outcome. Screening for IPA is indicated, easy to perform and a necessity to improve outcome.
Bioinformatics Unmasks the Maneuverers of Pain Pathways in Acute Kidney Injury
Authors: Gupta Aprajita , Puri Sanjeev , Puri Veena
Published: August 2019

Acute Kidney injury (AKI) is one of the leading health concerns resulting in accumulation of nitrogenous as well as non-nitrogenous wastes in body and characterised by a rapid deterioration in kidney functions. Besides the major toll from the primary insult in the kidney, consequential extra-renal secondary insults endowed with the pathways of inflammatory milieu often complicates the disease outcome. Some of the known symptoms of AKI leading to clinical reporting are fatigue, loss of appetite, headache, nausea, vomiting, and pain in the flanks, wherein proinflammatory cytokines have been strongly implicated in pathogenesis of AKI and neuro-inflammation. Taking in account these clues, we have tried to decode the neuro-inflammation and pain perception phenomenon during the progression of AKI using the pathway integration and biological network strategies. The pathways and networks were generated using bioinformatics software viz. PANTHER, Genomatix and PathVisio to establish the relationship between immune and neuro related pathway in AKI. These observations envisage a neurol-renal axis that is predicted to involve calcium channels in neuro-inflammatory pathway of AKI. These observations, thus, pave a way for a new paradigm in understanding the interplay of neuro-immunological signalling in AKI.
The effect of γ-FeOOH on enhancing arsenic adsorption from groundwater with DMAPAAQ + FeOOH gel composite
Authors: Safi Syed Ragib , Senmoto Kiyotaka , Gotoh Takehiko , Iizawa Takashi , Nakai Satoshi
Published: August 2019

Arsenic contamination of groundwater is a serious concern worldwide. The research gaps in removing arsenic are selectivity, regeneration and effective removal rate at neutral pH levels. In this study, we discussed the reasons of the high arsenic adsorption from groundwater of our previously developed adsorbent, a cationic polymer gel, N,N-dimethylamino propylacrylamide, methyl chloride quaternary (DMAPAAQ), loaded with iron hydroxide. We used a transmission electron microscope (TEM) and thermogravimetric analyser (TGA) to detect the iron contents in the gel and ensure its maximum impregnation. We found that the gel contains 62.05% FeOOH components. In addition, we used the Mössbauer spectroscopy to examine the type of impregnated iron in the gel composite and found that it was γ-FeOOH. Finally, we used Fourier transform infrared spectroscopy (FTIR) to examine the surface functional groups present in the gel and the differences in those groups before and after iron impregnation. Similarly, we also investigated the differences of the surface functional groups in the gel, before and after the adsorption of both forms of arsenic. To summarize, this study described the characteristics of the gel composite, which is selective in adsorption and cost effective, however further applications should be investigated.
Transcriptional alterations reveal Bacillus amyloliquefaciens-rice cooperation under salt stress
Authors: Chauhan Puneet Singh , Lata Charu , Tiwari Shalini , Chauhan Abhishek Singh , Mishra Shashank Kumar , Agrawal Lalit , Chakrabarty Debasis , Nautiyal Chandra Shekhar
Published: August 2019

The Bacillus amyloliquefaciens-SN13 and model crop rice (Oryza sativa) were chosen to understand the complex regulatory networks that govern plant-PGPR interaction under salt stress. During stress, inoculation with SN13 significantly increased biomass, relative water content, proline and total soluble sugar in rice while decreased lipid peroxidation and electrolyte leakage. Extensive alterations in gene expression were also observed in rice root transcriptome under stress in the presence of SN13. Rhizobacteria induced changes in expression of a considerable number of photosynthesis, hormone, and stress-responsive genes, in addition to cell-wall and lipid metabolism-related genes under salt stress as compared to salt stress or SN13 inoculation alone, indicating its potential role in reducing the harmful effects of salinity. To validate RNA-seq data, qRT-PCR was performed for selected differentially expressed genes representing various functional categories including metabolism, regulation, stress-response, and transporters. Results indicate qualitative and quantitative differences between roots responses to SN13 under stressed and unstressed conditions. Functional expressions of OsNAM and OsGRAM in yeast showed enhanced tolerance to various abiotic stresses, indicating crucial SN13-rice interaction in imparting beneficial effects under stress. This is first detailed report on understanding molecular mechanism underlying beneficial plant-microbe interaction in any economically important model crop plant under abiotic stress.
Comparing the Lifestyle Interventions for Prediabetes: An Integrated Microsimulation and Population Simulation Model
Authors: Khademi Amin , Shi Lu , Nasrollahzadeh Amir Ali , Narayanan Hariharaprabhu , Chen Liwei
Published: August 2019

We developed a model to compare the impacts of different lifestyle interventions among prediabetes individuals and to identify the optimal age groups for such interventions. A stochastic simulation was developed to replicate the prediabetes and diabetes trends (1997–2010) in the U.S. adult population. We then simulated the population-wide impacts of three lifestyle diabetes prevention programs, i.e., the Diabetes Prevention Program (DPP), DPP-YMCA, and the Healthy Living Partnerships to Prevent Diabetes (HELP-PD), over a course of 10, 15 and 30 years. Our model replicated the temporal trends of diabetes in the U.S. adult population. Compared to no intervention, the diabetes incidence declined 0.3 per 1,000 by DPP, 0.2 by DPP-YMCA, and 0.4 by HELP-PD over the 15-year period. Our simulations identified HELP-PD as the most cost-effective intervention, which achieved the highest 10-year savings of $38 billion for those aged 25–65, assuming all eligible individuals participate in the intervention and considering intervention achievement rates. Our model simulates the diabetes trends in the U.S. population based on individual-level longitudinal data. However, it may be used to identify the optimal intervention for different subgroups in defined populations.
In vitro exercise model using contractile human and mouse hybrid myotubes
Authors: Chen Weijian , Nyasha Mazvita R. , Koide Masashi , Tsuchiya Masahiro , Suzuki Naoki , Hagiwara Yoshihiro , Aoki Masashi , Kanzaki Makoto
Published: August 2019

Contraction of cultured myotubes with application of electric pulse stimulation (EPS) has been utilized for investigating cellular responses associated with actual contractile activity. However, cultured myotubes derived from human subjects often exhibit relatively poor EPS-evoked contractile activity, resulting in minimal contraction-inducible responses (i.e. myokine secretion). We herein describe an “in vitro exercise model”, using hybrid myotubes comprised of human myoblasts and murine C2C12 myoblasts, exhibiting vigorous contractile activity in response to EPS. Species-specific analyses including RT-PCR and the BioPlex assay allowed us to separately evaluate contraction-inducible gene expressions and myokine secretions from human and mouse constituents of hybrid myotubes. The hybrid myotubes, half of which had arisen from primary human satellite cells obtained from biopsy samples, exhibited remarkable increases in the secretions of human cytokines (myokines) including interleukins (IL-6, IL-8, IL-10, and IL16), CXC chemokines (CXCL1, CXCL2, CXCL5, CXCL6, CXCL10), CC chemokines (CCL1, CCL2, CCL7, CCL8, CCL11, CCL13, CCL16, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL27), and IFN-γ in response to EPS-evoked contractile activity. Together, these results indicate that inadequacies arising from human muscle cells are effectively overcome by fusing them with murine C2C12 cells, thereby supporting the development of contractility and the resulting cellular responses of human-origin muscle cells. Our approach, using hybrid myotubes, further expands the usefulness of the “in vitro exercise model”.
Structural design of microbicidal cationic oligomers and their synergistic interaction with azoles against Candida albicans
Authors: Yuan Yuan , Zhou Feng , Su Haibin , Zhang Yugen
Published: August 2019

Membrane-disrupting synthetic antimicrobial polymers have been well developed as antimicrobial peptide (AMP) mimics to mitigate antimicrobial resistance (AMR). However, synthetic polymers possess inherent drawbacks, being a mixture of different chain lengths, which restricts their clinical applications. In fact, synthetic oligomers with defined chain length and molecular structure could be better representatives of AMPs. Herein, a series of novel imidazolium-ammonium oligomers developed in this work exhibit excellent broad spectrum antimicrobial activity, specifically the salient structure dependent high efficiency against C. albicans. Moreover, synergistic effect emerged when the combined azoles and synthetic oligomers were applied against C. albicans. The detail structural coupling between azoles and oligomers was scrutinized through molecular dynamics simulations to unravel the interaction details with the atomistic resolution. The labile interaction between oligomer and azoles facilitated the transfer of drug into fungal cells, which can be a synergistic solution to prevent the development of resistance on C. albicans.
Berberine improved experimental chronic colitis by regulating interferon-γ- and IL-17A-producing lamina propria CD4+ T cells through AMPK activation
Authors: Takahara Masahiro , Takaki Akinobu , Hiraoka Sakiko , Adachi Takuya , Shimomura Yasuyuki , Matsushita Hiroshi , Nguyen Tien Thi Thuy , Koike Kazuko , Ikeda Airi , Takashima Shiho , Yamasaki Yasushi , Inokuchi Toshihiro , Kinugasa Hideaki , Sugihara Yusaku , Harada Keita , Eikawa Shingo , Morita Hidetoshi , Udono Heiichiro , Okada Hiroyuki
Published: August 2019

The herbal medicine berberine (BBR) has been recently shown to be an AMP-activated protein kinase (AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4+T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). We examined the favorable effects of BBR in vitro, using lamina propria (LP) CD4+ T cells in T cell transfer IBD models in which SCID mice had been injected with CD4+CD45RBhigh T cells. BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4+ T cells. This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. We then examined the effects of BBR on the same IBD models in vivo. BBR-fed mice showed AMPK activation in the LPCD4+ T cells and an improvement of colitis. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4+ T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation.
The NRON complex controls circadian clock function through regulated PER and CRY nuclear translocation
Authors: Lee Yool , Shen Yang , Francey Lauren J. , Ramanathan Chidambaram , Sehgal Amita , Liu Andrew C. , Hogenesch John B.
Published: August 2019

Post-translational regulation plays a central role in the circadian clock mechanism. However, nucleocytoplasmic translocation of core clock proteins, a key step in circadian timekeeping, is not fully understood. Earlier we found that the NRON scaffolding complex regulates nuclear translocation of NFAT and its signaling. Here, we show that components of the NRON complex also regulate the circadian clock. In peripheral cell clock models, genetic perturbation of the NRON complex affects PER and CRY protein nuclear translocation, dampens amplitude, and alters period length. Further, we show small molecules targeting the NFAT pathway alter nuclear translocation of PER and CRY proteins and impact circadian rhythms in peripheral cells and tissue explants of the master clock in the suprachiasmatic nucleus. Taken together, these studies highlight a key role for the NRON complex in regulating PER/CRY subcellular localization and circadian timekeeping.
Welfare-improving enrichments greatly reduce hens’ startle responses, despite little change in judgment bias
Authors: Ross Misha , Garland Anna , Harlander-Matauschek Alexandra , Kitchenham Lindsey , Mason Georgia
Published: August 2019

Responses to ambiguous and aversive stimuli (e.g. via tests of judgment bias and measures of startle amplitude) can indicate mammals’ affective states. We hypothesised that such findings generalize to birds, and that these two responses co-vary (since both involve stimulus evaluation). To validate startle reflexes (involuntary responses to sudden aversive stimuli) and responses in a judgment bias task as indicators of avian affective state, we differentially housed hens with or without preferred enrichments assumed to improve mood (in a crossover design). To control for personality, we first measured hens’ baseline exploration levels. To infer judgment bias, control and enriched hens were trained to discriminate between white and dark grey cues (associated with reward and punishment, respectively), and then probed with intermediate shades of grey. For startle reflexes, forceplates assessed responses to a light flash. Judgment bias was only partially validated: Exploratory hens showed more ‘optimism’ when enriched, but Non-exploratory hens did not. Across all birds, however, startle amplitudes were dramatically reduced by enrichment (albeit more strongly in Exploratory subjects): the first evidence that avian startle is affectively modulated. Startle and judgment biases did not co-vary, suggesting different underlying mechanisms. Of the two measures, startle reflexes thus seem most sensitive to avian affective state.
The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER
Authors: Carvalho Hugo J. F. , Del Bondio Andrea , Maltecca Francesca , Colombo Sara F. , Borgese Nica
Published: August 2019

Calcium-modulating cyclophilin ligand (CAML), together with Tryptophan rich basic protein (WRB, Get1 in yeast), constitutes the mammalian receptor for the Transmembrane Recognition Complex subunit of 40 kDa (TRC40, Get3 in yeast), a cytosolic ATPase with a central role in the post-translational targeting pathway of tail-anchored (TA) proteins to the endoplasmic reticulum (ER) membrane. CAML has also been implicated in other cell-specific processes, notably in immune cell survival, and has been found in molar excess over WRB in different cell types. Notwithstanding the stoichiometric imbalance, WRB and CAML depend strictly on each other for expression. Here, we investigated the mechanism by which WRB impacts CAML levels. We demonstrate that CAML, generated in the presence of sufficient WRB levels, is inserted into the ER membrane with three transmembrane segments (TMs) in its C-terminal region. By contrast, without sufficient levels of WRB, CAML fails to adopt this topology, and is instead incompletely integrated to generate two aberrant topoforms; these congregate in ER-associated clusters and are degraded by the proteasome. Our results suggest that WRB, a member of the recently proposed Oxa1 superfamily, acts catalytically to assist the topogenesis of CAML and may have wider functions in membrane biogenesis than previously appreciated.
Non-professional phagocytosis: a general feature of normal tissue cells
Authors: Seeberg Jacob C. , Loibl Monika , Moser Fabian , Schwegler Manuela , Büttner-Herold Maike , Daniel Christoph , Engel Felix B. , Hartmann Arndt , Schlötzer-Schrehardt Ursula , Goppelt-Struebe Margarete , Schellerer Vera , Naschberger Elisabeth , Ganzleben Ingo , Heinzerling Lucie , Fietkau Rainer , Distel Luitpold V.
Published: August 2019

Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
Experimental test of the collapse time of a delocalized photon state
Authors: Garrisi Francesco , Massara Micol Previde , Zambianchi Alberto , Galli Matteo , Bajoni Daniele , Rimini Alberto , Nicrosini Oreste
Published: August 2019

We investigate whether the collapse of the quantum state of a single photon split between two space-like separated places takes a nonvanishing time. We realize this by using a source of heralded single photons, then splitting the resulting single photon state and letting it propagate over distances much larger than the experimental time resolution times the speed of light c. We find no additional delay within our accuracy and set a lower limit for the speed of collapse of the quantum state to 1550c.
The role of the refractory period in diapause length determination in a freshwater crustacean
Authors: Ślusarczyk Mirosław , Chlebicki Wojciech , Pijanowska Joanna , Radzikowski Jacek
Published: August 2019

We investigate here the mechanism of allochronic resumption of development by the dormant forms in organisms inhabiting temporary habitats. The cohorts of resting eggs of a short living freshwater crustacean Daphnia magna collected in two temporary waters at two occasions (spring and autumn) were exposed after different storage periods (0–16 weeks) spent either in wet or dry conditions to a given set of hatching stimuli announcing appearance of favourable conditions. Freshly formed resting eggs did not hatch or hatched occasionally. The resting eggs formed in autumn hatched more eagerly than the spring ones when exposed to favourable conditions after wet storage. The hatching proportion increased linearly up to 68–82% in autumn resting eggs while to 33–44% in the spring ones over 16 weeks of storage that might have covered several generations of the active forms. Dry storage of the resting eggs reduced their hatching proportion considerably. We suspect that the length variation of a refractory period (initial phase of developmental arrest when resting forms remain insensitive to hatching stimuli) followed by a reactivation period may constitute the simplest two-step physiological mechanism allowing staggering revival of the dormant forms in subsequent generations that maximise chances for survival in unpredictably changing habitats.
The burdens of tuberculosis on patients with malignancy: incidence, mortality and relapse
Authors: Shu Chin-Chung , Liao Kuang-Ming , Chen Yi-Chen , Wang Jhi-Joung , Ho Chung-Han
Published: August 2019

Population with malignancy is growing worldwide; however, its tuberculosis (TB) burden including remains unclear regarding incidence, mortality, and relapse. We retrieved information and identified patients with malignancy and TB between 2000 and 2015 from the Taiwanese National Health Insurance reimbursement datasets, Taiwan cancer registry and death registration. We analyzed the incidence of new TB in patients with malignancy and their mortality as well as TB recurrence. During study period, we reviewed 1,105,009 patients after exclusion and among them, 19,906 had newly diagnosed TB. The TB incidence in cancer patients divided all TB events increased annually, from 3% in 2000 to 13% in 2015. The standard incidence rates (SIR) were highest in cancer of respiratory tract (5.45), hematology (3.70) and then head and neck area (2.58). The mortality directly due to TB was defined as 0.83% and all-cause mortality were approximately 10.5% at 3 months and 20.56% at 12 months. After completing TB treatment, recurrence was diagnosed in 626 (3.14%), and 1001 (5.03%) patients within the first and the first two years, respectively. In conclusion, the incidence of TB in patients with malignancy increase yearly as well as its proportion within overall cases. The twelve-month all-cause mortality during TB and the two-year recurrence are as high as 20.56% and 5.03%, respectively. It indicates the importance of this population in future TB control, especially for those with malignancy of respiratory tract, and hematology as well as head and neck area.