bluuebunny/crossref_metadata_2025 huggingface dataset:
Clustering Surface Ozone Diurnal Cycles to Understand the Impact of Circulation Patterns in Houston, TX
Authors: Bernier Claudia , Wang Yuxuan , Estes Mark , Lei Ruixue , Jia Beixi , Wang Sing‐Chun , Sun Jiajia
Published: November 2019

The diurnal cycle of surface ozone is directly influenced by the chemistry and meteorological processes which affect a region. This study uniquely employs a clustering methodology to examine the complete diurnal pattern of surface ozone for the Houston‐Galveston‐Brazoria region and links the identified patterns to meteorological regimes for June, July, and August of 3 years (2011, 2014, and 2015). Four features were implemented into the clustering algorithm: ozone rate of decrease at night, daily minimum before sunrise, rate of increase after sunrise, and an average of afternoon ozone. Four clusters were chosen, ranging from a mostly flat diurnal pattern with low mixing ratios (~20 ppbv) throughout the day (Cluster 1), to a more variable diurnal cycle with very high mixing ratios (>70 ppbv) in the afternoon (Cluster 4). The clusters are found to associate with distinctive circulation patterns and well‐known regional meteorological processes, such as the low‐level jet and Bermuda High. The uneven distribution of the clusters between the years helps elucidate ozone interannual variability due to meteorology: Cluster 4 had 0 days assigned from 2014 due to the greater influence of circulation patterns bringing clean air from the Gulf of Mexico. We show that the clustering method better characterizes ozone variability than the simplistic method of dividing peak ozone into quantiles. With the clustering analysis, we demonstrate that the ozone diurnal pattern holds more value than just peak ozone hours of the day in providing a clearer understanding of ozone variability and associated meteorological processes.
Introduction to the Water‐Soil‐Air‐Plant‐Human Nexus: Modeling and Observing Complex Land Surface Systems at River Basin Scale
Authors: Li Xin , Xie Zhenghui
Published: November 2019

Bidirectional coupling of complex human‐nature system can be referred to as water‐soil‐air‐plant‐human nexus, and integrated studies of this nexus have been carried out in many river basins around the world. This special issue reports contributions for modeling, observing, and understanding of water‐soil‐air‐plant‐human nexus at river basin scale, particularly those from the “Integrated research on the eco‐hydrological process of the Heihe River Basin” program. This paper highlights key results as an introduction to the special issue.
Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis
Authors: Kennis Mitzy , Gerritsen Lotte , van Dalen Marije , Williams Alishia , Cuijpers Pim , Bockting Claudi
Published: November 2019

Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress. Searches were performed in Pubmed, Embase and PsychInfo for articles published up to 06/2019. References and citations of included articles were screened to identify additional articles. Inclusion criteria were having an MDD diagnosis as outcome, a biomarker as predictor, and prospective design search terms were formulated accordingly. PRISMA guidelines were applied. Meta-analyses were performed using a random effect model when three or more comparable studies were identified, using a random effect model. Our search resulted in 67,464 articles, of which 75 prospective articles were identified on: Neuroimaging (N = 24), Gastrointestinal factors (N = 1), Immunology (N = 8), Neurotrophic (N = 2), Neurotransmitters (N = 1), Hormones (N = 39), Oxidative stress (N = 1). Meta-analyses on brain volumes and immunology markers were not significant. Only cortisol (N = 19, OR = 1.294,p = 0.024) showed a predictive effect on onset/relapse/recurrence of MDD, but not on time until MDD onset/relapse/recurrence. However, this effect disappeared when studies including participants with a baseline clinical diagnosis were removed from the analyses. Other studies were too heterogeneous to compare. Thus, there is a lack of evidence for leading biological theories for onset and maintenance of depression. Only cortisol was identified as potential predictor for MDD, but results are influenced by the disease state. High-quality (prospective) studies on MDD are needed to disentangle the etiology and maintenance of MDD.
A Bayesian machine learning approach for drug target identification using diverse data types
Authors: Madhukar Neel S. , Khade Prashant K. , Huang Linda , Gayvert Kaitlyn , Galletti Giuseppe , Stogniew Martin , Allen Joshua E. , Giannakakou Paraskevi , Elemento Olivier
Published: November 2019

Drug target identification is a crucial step in development, yet is also among the most complex. To address this, we develop BANDIT, a Bayesian machine-learning approach that integrates multiple data types to predict drug binding targets. Integrating public data, BANDIT benchmarked a ~90% accuracy on 2000+ small molecules. Applied to 14,000+ compounds without known targets, BANDIT generated ~4,000 previously unknown molecule-target predictions. From this set we validate 14 novel microtubule inhibitors, including 3 with activity on resistant cancer cells. We applied BANDIT to ONC201—an anti-cancer compound in clinical development whose target had remained elusive. We identified and validated DRD2 as ONC201’s target, and this information is now being used for precise clinical trial design. Finally, BANDIT identifies connections between different drug classes, elucidating previously unexplained clinical observations and suggesting new drug repositioning opportunities. Overall, BANDIT represents an efficient and accurate platform to accelerate drug discovery and direct clinical application.
Single-atom cobalt array bound to distorted 1T MoS2 with ensemble effect for hydrogen evolution catalysis
Authors: Qi Kun , Cui Xiaoqiang , Gu Lin , Yu Shansheng , Fan Xiaofeng , Luo Mingchuan , Xu Shan , Li Ningbo , Zheng Lirong , Zhang Qinghua , Ma Jingyuan , Gong Yue , Lv Fan , Wang Kai , Huang Haihua , Zhang Wei , Guo Shaojun , Zheng Weitao , Liu Ping
Published: November 2019

The grand challenge in the development of atomically dispersed metallic catalysts is their low metal-atom loading density, uncontrollable localization and ambiguous interactions with supports, posing difficulty in maximizing their catalytic performance. Here, we achieve an interface catalyst consisting of atomic cobalt array covalently bound to distorted 1T MoS2 nanosheets (SA Co-D 1T MoS2). The phase of MoS2 transforming from 2H to D-1T, induced by strain from lattice mismatch and formation of Co-S covalent bond between Co and MoS2 during the assembly, is found to be essential to form the highly active single-atom array catalyst. SA Co-D 1T MoS2 achieves Pt-like activity toward HER and high long-term stability. Active-site blocking experiment together with density functional theory (DFT) calculations reveal that the superior catalytic behaviour is associated with an ensemble effect via the synergy of Co adatom and S of the D-1T MoS2 support by tuning hydrogen binding mode at the interface.
Transposable element expression in tumors is associated with immune infiltration and increased antigenicity
Authors: Kong Yu , Rose Christopher M. , Cass Ashley A. , Williams Alexander G. , Darwish Martine , Lianoglou Steve , Haverty Peter M. , Tong Ann-Jay , Blanchette Craig , Albert Matthew L. , Mellman Ira , Bourgon Richard , Greally John , Jhunjhunwala Suchit , Chen-Harris Haiyin
Published: November 2019

Profound global loss of DNA methylation is a hallmark of many cancers. One potential consequence of this is the reactivation of transposable elements (TEs) which could stimulate the immune system via cell-intrinsic antiviral responses. Here, we developREdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observe increased expression of over 400 TE subfamilies, of which 262 appear to result from a proximal loss of DNA methylation. The most recurrent TEs are among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent results in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing inflammation and the display of potentially immunogenic neoantigens.
Molecular mechanisms underlying phytochrome-controlled morphogenesis in plants
Authors: Legris Martina , Ince Yetkin Çaka , Fankhauser Christian
Published: November 2019

Phytochromes are bilin-binding photosensory receptors which control development over a broad range of environmental conditions and throughout the whole plant life cycle. Light-induced conformational changes enable phytochromes to interact with signaling partners, in particular transcription factors or proteins that regulate them, resulting in large-scale transcriptional reprograming. Phytochromes also regulate promoter usage, mRNA splicing and translation through less defined routes. In this review we summarize our current understanding of plant phytochrome signaling, emphasizing recent work performed in Arabidopsis. We compare and contrast phytochrome responses and signaling mechanisms among land plants and highlight open questions in phytochrome research.
Environmental co-benefits and adverse side-effects of alternative power sector decarbonization strategies
Authors: Luderer Gunnar , Pehl Michaja , Arvesen Anders , Gibon Thomas , Bodirsky Benjamin L. , de Boer Harmen Sytze , Fricko Oliver , Hejazi Mohamad , Humpenöder Florian , Iyer Gokul , Mima Silvana , Mouratiadou Ioanna , Pietzcker Robert C. , Popp Alexander , van den Berg Maarten , van Vuuren Detlef , Hertwich Edgar G.
Published: November 2019

A rapid and deep decarbonization of power supply worldwide is required to limit global warming to well below 2 °C. Beyond greenhouse gas emissions, the power sector is also responsible for numerous other environmental impacts. Here we combine scenarios from integrated assessment models with a forward-looking life-cycle assessment to explore how alternative technology choices in power sector decarbonization pathways compare in terms of non-climate environmental impacts at the system level. While all decarbonization pathways yield major environmental co-benefits, we find that the scale of co-benefits as well as profiles of adverse side-effects depend strongly on technology choice. Mitigation scenarios focusing on wind and solar power are more effective in reducing human health impacts compared to those with low renewable energy, while inducing a more pronounced shift away from fossil and toward mineral resource depletion. Conversely, non-climate ecosystem damages are highly uncertain but tend to increase, chiefly due to land requirements for bioenergy.
A morphogenetic EphB/EphrinB code controls hepatopancreatic duct formation
Authors: Thestrup M. Ilcim , Caviglia Sara , Cayuso Jordi , Heyne Ronja L. S. , Ahmad Racha , Hofmeister Wolfgang , Satriano Letizia , Wilkinson David G. , Andersen Jesper B. , Ober Elke A.
Published: November 2019

The hepatopancreatic ductal (HPD) system connects the intrahepatic and intrapancreatic ducts to the intestine and ensures the afferent transport of the bile and pancreatic enzymes. Yet the molecular and cellular mechanisms controlling their differentiation and morphogenesis into a functional ductal system are poorly understood. Here, we characterize HPD system morphogenesis by high-resolution microscopy in zebrafish. The HPD system differentiates from a rod of unpolarized cells into mature ducts by de novo lumen formation in a dynamic multi-step process. The remodeling step from multiple nascent lumina into a single lumen requires active cell intercalation and myosin contractility. We identify key functions for EphB/EphrinB signaling in this dynamic remodeling step. Two EphrinB ligands, EphrinB1 and EphrinB2a, and two EphB receptors, EphB3b and EphB4a, control HPD morphogenesis by remodeling individual ductal compartments, and thereby coordinate the morphogenesis of this multi-compartment ductal system.
Regulatory effect of two Trichinella spiralis serine protease inhibitors on the host’s immune system
Authors: Xu Jingyun , Yu Pengcheng , Wu Lijia , Liu Mingxu , Lu Yixin
Published: November 2019

Trichinella spiralis (T. spiralis) is widely distributed throughout the world and can cause serious zoonotic parasitic diseases. Serine protease inhibitors (SPIs) have unique enzyme inhibitory activity and occupy an important position in the interaction between parasites and hosts. In order to further understand the immunoprotective effect of SPIs on T. spiralis invasion in vivo, the Kazal and Serpin type SPI of T. spiralis (TsKaSPI and TsAdSPI) were mixed with Freund’s adjuvant in equal volume to immunize mice. The results showed that the expression of IgG1 and IgG2a in serum, the proliferation of spleen cells, and the expression level of cytokines were all increased. The results of flow cytometry showed that the expression of CD4+CD25+Foxp3+ Tregs, CD8+CD28− T cells, CD19+CD5+CD1dhi Bregs in spleen were also increased. Therefore, both TsKaSPI and TsAdSPI could induce strong humoral and cellular immune responses. And the results of adult reduction rate and pathological changes of intestine after adult invasion also indicated that both TsKaSPI and TsAdSPI could prevent T. spiralis from invading intestine. To explore the regulatory effects of TsKaSPI and TsAdSPI on the immune function of macrophage, the results of ELISA showed that the expression of cytokines in cell supernatant were increased. And the results of Western blot showed that both TsKaSPI and TsAdSPI could induce phosphorylation of JAK2 and STAT3 receptors, thereby affecting the signal transduction of macrophages. This experiment demonstrated that SPIs could act as effector molecules affecting the immune function of host when infected with T. spiralis.
Identification of lipid A deacylase as a novel, highly conserved and protective antigen against enterohemorrhagic Escherichia coli
Authors: Rojas-Lopez Maricarmen , Martinelli Manuele , Brandi Valentina , Jubelin Grégory , Polticelli Fabio , Soriani Marco , Pizza Mariagrazia , Desvaux Mickaël , Rosini Roberto
Published: November 2019

Enterohemorrhagic E. coli (EHEC) is a major cause of large outbreaks worldwide associated with hemorrhagic colitis and hemolytic uremic syndrome. While vaccine development is warranted, a licensed vaccine, specific for human use, against EHEC is not yet available. In this study, the reverse vaccinology approach combined with genomic, transcriptional and molecular epidemiology data was applied on the EHEC O157:H7 genome to select new potential vaccine candidates. Twenty-four potential protein antigens were identified and one of them (MC001) was successfully expressed onto Generalized Modules for Membrane Antigens (GMMA) delivery system. GMMA expressing this vaccine candidate was immunogenic, raising a specific antibody response. Immunization with the MC001 candidate was able to reduce the bacterial load of EHEC O157:H7 strain in feces, colon and caecum tissues after murine infection. MC001 is homologue to lipid A deacylase enzyme (LpxR), and to our knowledge, this is the first study describing it as a potential vaccine candidate. Gene distribution and sequence variability analysis showed that MC001 is present and conserved in EHEC and in enteropathogenic E. coli (EPEC) strains. Given the high genetic variability among and within E. coli pathotypes, the identification of such conserved antigen suggests that its inclusion in a vaccine might represent a solution against major intestinal pathogenic strains.
Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate
Authors: Krucinska Jolanta , Lombardo Michael N. , Erlandsen Heidi , Hazeen Akram , Duay Searle S. , Pattis Jason G. , Robinson Victoria L. , May Eric R. , Wright Dennis L.
Published: November 2019

Many years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery.
Field cress genome mapping: Integrating linkage and comparative maps with cytogenetic analysis for rDNA carrying chromosomes
Authors: Desta Zeratsion Abera , Kolano Bozena , Shamim Zeeshan , Armstrong Susan J. , Rewers Monika , Sliwinska Elwira , Kushwaha Sandeep Kumar , Parkin Isobel A. P. , Ortiz Rodomiro , de Koning Dirk-Jan
Published: November 2019

Field cress (Lepidium campestreL.), despite its potential as a sustainable alternative oilseed plant, has been underutilized, and no prior attempts to characterize the genome at the genetic or molecular cytogenetic level have been conducted. Genetic maps are the foundation for anchoring and orienting annotated genome assemblies and positional cloning of candidate genes. Our principal goal was to construct a genetic map using integrated approaches of genetic, comparative and cytogenetic map analyses. In total, 503 F2interspecific hybrid individuals were genotyped using 7,624 single nucleotide polymorphism markers. Comparative analysis demonstrated that ~57% of the sequenced loci inL. campestrewere congruent withArabidopsis thaliana(L.) genome and suggested a novel karyotype, which predates the ancestral crucifer karyotype. Aceto-orcein chromosome staining and fluorescencein situhybridization (FISH) analyses confirmed thatL. campestre,L. heterophyllumBenth. and their hybrids had a chromosome number of 2n = 2x = 16. Flow cytometric analysis revealed that both species possess 2C roughly 0.4 picogram DNA. Integrating linkage and comparative maps with cytogenetic map analyses assigned two linkage groups to their particular chromosomes. Future work could incorporate FISH utilizingA. thalianamapped BAC clones to allow the chromosomes of field cress to be identified reliably.
Clinical impact of low serum free T4 in patients with non-small cell lung cancer treated with nivolumab
Authors: Funazo Tomoko Yamamoto , Nomizo Takashi , Ozasa Hiroaki , Tsuji Takahiro , Yasuda Yuto , Yoshida Hironori , Sakamori Yuichi , Nagai Hiroki , Hirai Toyohiro , Kim Young Hak
Published: November 2019

Nivolumab improves the prognosis of non-small cell lung cancer (NSCLC) but can cause immune-related adverse events (irAEs). Reports have indicated longer progression-free survivals (PFSs) in patients with irAEs than in those without irAEs. We reported associations between programmed death ligand-1 (PD-L1) single nucleotide polymorphisms (SNPs) and PFS after nivolumab treatment. We hypothesized that adverse events might be associated with the SNPs of PD-L1. We analyzed data from 111 patients with NSCLC treated with nivolumab. The response rate was 14%, and the median PFS was 68 days. We found patients with the adverse event of low free tetraiodothyronine (fT4) had significantly longer PFSs than those without low fT4 (not reached vs 67 days; hazard ratio [HR], 0.297; P = 0.010). Moreover, median overall survival was longer in patients with low fT4 than those without low fT4 (not reached vs 556 days, HR, 0.139; P = 0.020). Patients with the T allele of rs1411262 (P = 0.0073) and with the A allele of rs822339 (P = 0.0204) developed low fT4. Patients with the T/T genotype had longer PFSs than with those with the C/T and C/C genotypes of rs1411262 (165 vs. 67 days, HR, 1.65; P = 0.040), and those with the A/A genotype had longer PFSs than those with the A/G and G/G genotypes of rs822339 (182 vs. 67 days, HR, 1.76; P = 0.025). In the patients with advanced NSCLC, low fT4 after nivolumab treatment was associated with significantly longer PFSs. The SNPs of PD-L1 may be associated with the adverse events of nivolumab.
Monolayer MoS2 field effect transistor with low Schottky barrier height with ferromagnetic metal contacts
Authors: Gupta Sachin , Rortais F. , Ohshima R. , Ando Y. , Endo T. , Miyata Y. , Shiraishi M.
Published: November 2019

Two-dimensional MoS2 has emerged as promising material for nanoelectronics and spintronics due to its exotic properties. However, high contact resistance at metal semiconductor MoS2 interface still remains an open issue. Here, we report electronic properties of field effect transistor devices using monolayer MoS2 channels and permalloy (Py) as ferromagnetic (FM) metal contacts. Monolayer MoS2 channels were directly grown on SiO2/Si substrate via chemical vapor deposition technique. The increase in current with back gate voltage (Vg) shows the tunability of FET characteristics. The Schottky barrier height (SBH) estimated for Py/MoS2 contacts is found to be +28.8 meV (at Vg = 0V), which is the smallest value reported so-far for any direct metal (magnetic or non-magnetic)/monolayer MoS2 contact. With the application of positive gate voltage, SBH shows a reduction, which reveals ohmic behavior of Py/MoS2 contacts. Low SBH with controlled ohmic nature of FM contacts is a primary requirement for MoS2 based spintronics and therefore using directly grown MoS2 channels in the present study can pave a path towards high performance devices for large scale applications.
Continuation of tropical Pacific Ocean temperature trend may weaken extreme El Niño and its linkage to the Southern Annular Mode
Authors: Lim Eun-Pa , Hendon Harry H. , Hope Pandora , Chung Christine , Delage Francois , McPhaden Michael J.
Published: November 2019

Observational records show that occurrences of the negative polarity of the Southern Annular Mode (low SAM) is significantly linked to El Niño during austral spring and summer, potentially providing long-lead predictability of the SAM and its associated surface climate conditions. In this study, we explore how this linkage may change under a scenario of a continuation of the ocean temperature trends that have been observed over the past 60 years, which are plausibly forced by increasing greenhouse gas concentrations. We generated coupled model seasonal forecasts for three recent extreme El Niño events by initialising the forecasts with observed ocean anomalies of 1 September 1982, 1997 and 2015 added into (1) the current ocean mean state and into (2) the ocean mean state updated to include double the recent ocean temperature trends. We show that the strength of extreme El Niño is reduced with the warmer ocean mean state as a result of reduced thermocline feedback and weakened rainfall-wind-sea surface temperature coupling over the tropical eastern Pacific. The El Niño-low SAM relationship also weakens, implying the possibility of reduced long-lead predictability of the SAM and associated surface climate impacts in the future.
The burden of submicroscopic and asymptomatic malaria in India revealed from epidemiology studies at three varied transmission sites in India
Authors: van Eijk Anna Maria , Sutton Patrick L. , Ramanathapuram Lalitha , Sullivan Steven A. , Kanagaraj Deena , Priya G. Sri Lakshmi , Ravishankaran Sangamithra , Asokan Aswin , Sangeetha V. , Rao Pavitra N. , Wassmer Samuel C. , Tandel Nikunj , Patel Ankita , Desai Nisha , Choubey Sandhya , Ali Syed Zeeshan , Barla Punam , Oraon Rajashri Rani , Mohanty Stuti , Mishra Shobhna , Kale Sonal , Bandyopadhyay Nabamita , Mallick Prashant K. , Huck Jonathan , Valecha Neena , Singh Om P. , Pradhan K. , Singh Ranvir , Sharma S. K. , Srivastava Harish C. , Carlton Jane M. , Eapen Alex
Published: November 2019

Malaria in India, while decreasing, remains a serious public health problem, and the contribution of submicroscopic and asymptomatic infections to its persistence is poorly understood. We conducted community surveys and clinic studies at three sites in India differing in their eco-epidemiologies: Chennai (Tamil Nadu), Nadiad (Gujarat), and Rourkela (Odisha), during 2012–2015. A total of 6,645 subject blood samples were collected for Plasmodium diagnosis by microscopy and PCR, and an extensive clinical questionnaire completed. Malaria prevalence ranged from 3–8% by PCR in community surveys (24 infections in Chennai, 56 in Nadiad, 101 in Rourkela), with Plasmodium vivax dominating in Chennai (70.8%) and Nadiad (67.9%), and Plasmodium falciparum in Rourkela (77.3%). A proportional high burden of asymptomatic and submicroscopic infections was detected in community surveys in Chennai (71% and 71%, respectively, 17 infections for both) and Rourkela (64% and 31%, 65 and 31 infections, respectively). In clinic studies, a proportional high burden of infections was identified as submicroscopic in Rourkela (45%, 42 infections) and Chennai (19%, 42 infections). In the community surveys, anemia and fever were significantly more common among microscopic than submicroscopic infections. Exploratory spatial analysis identified a number of potential malaria hotspots at all three sites. There is a considerable burden of submicroscopic and asymptomatic malaria in malarious regions in India, which may act as a reservoir with implications for malaria elimination strategies.
Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson’s disease
Authors: Voronin Mikhail V. , Kadnikov Ilya A. , Voronkov Dmitry N. , Seredenin Sergey B.
Published: November 2019

Parkinson’s disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson’s disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.
Inferring correlations associated to causal interactions in brain signals using autoregressive models
Authors: López-Madrona Víctor J. , Matias Fernanda S. , Mirasso Claudio R. , Canals Santiago , Pereda Ernesto
Published: November 2019

The specific connectivity of a neuronal network is reflected in the dynamics of the signals recorded on its nodes. The analysis of how the activity in one node predicts the behaviour of another gives the directionality in their relationship. However, each node is composed of many different elements which define the properties of the links. For instance, excitatory and inhibitory neuronal subtypes determine the functionality of the connection. Classic indexes such as the Granger causality (GC) quantifies these interactions, but they do not infer into the mechanism behind them. Here, we introduce an extension of the well-known GC that analyses the correlation associated to the specific influence that a transmitter node has over the receiver. This way, the G-causal link has a positive or negative effect if the predicted activity follows directly or inversely, respectively, the dynamics of the sender. The method is validated in a neuronal population model, testing the paradigm that excitatory and inhibitory neurons have a differential effect in the connectivity. Our approach correctly infers the positive or negative coupling produced by different types of neurons. Our results suggest that the proposed approach provides additional information on the characterization of G-causal connections, which is potentially relevant when it comes to understanding interactions in the brain circuits.
Gold-Hybridized Zinc Oxide Nanorods as Real-Time Low-Cost NanoBiosensors for Detection of virulent DNA signature of HPV-16 in Cervical Carcinoma
Authors: Ramesh Thevendran , Foo Kai Loong , R. Haarindraprasad , Sam Annie Jeyachristy , Solayappan Maheswaran
Published: November 2019

Detection of host integrated viral oncogenes are critical for early and point-of-care molecular diagnostics of virus-induced carcinoma. However, available diagnostic approaches are incapable of combining both cost-efficient medical diagnosis and high analytical performances. To circumvent this, we have developed an improved IDE-based nanobiosensor for biorecognition of HPV-16 infected cervical cancer cells through electrochemical impedance spectroscopy. The system is fabricated by coating gold (Au) doped zinc oxide (ZnO) nanorods interfaced with HPV-16 viral DNA bioreceptors on top of the Interdigitated Electrode (IDE) chips surface. Due to the concurrently improved sensitivity and biocompatibility of the designed nanohybrid film, Au decorated ZnO-Nanorod biosensors demonstrate exceptional detection of HPV-16 E6 oncogene, the cancer biomarker for HPV infected cervical cancers. This sensor displayed high levels of sensitivity by detecting as low as 1fM of viral E6 gene target. The sensor also exhibited a stable functional life span of more than 5 weeks, good reproducibility and high discriminatory properties against HPV-16. Sensor current responses are obtained from cultured cervical cancer cells which are close to clinical cancer samples. Hence, the developed sensor is an adaptable tool with high potential for clinical diagnosis especially useful for economically challenged countries/regions.
Fanconi anemia proteins counteract the implementation of the oncogene-induced senescence program
Authors: Helbling-Leclerc Anne , Dessarps-Freichey Françoise , Evrard Caroline , Rosselli Filippo
Published: November 2019

Fanconi Anemia (FA), due to the loss-of-function of the proteins that constitute the FANC pathway involved in DNA replication and genetic stability maintainance, is a rare genetic disease featuring bone marrow failure, developmental abnormalities and cancer predisposition. Similar clinical stigmas have also been associated with alterations in the senescence program, which is activated in physiological or stress situations, including the unscheduled, chronic, activation of an oncogene (oncogene induced senescence, OIS). Here, we wanted to determine the crosstalk, if any, between the FANC pathway and the OIS process. OIS was analyzed in two known cellular models, IMR90-hTERT/ER:RASG12V and WI38-hTERT/ER:GFP:RAF1, harboring 4-hydroxytamoxifen-inducible oncogenes. We observed that oncogene activation induces a transitory increase of both FANCA and FANCD2 as well as FANCD2 monoubiquitination, readout of FANC pathway activation, followed by their degradation. FANCD2 depletion, which leads to a pre-senescent phenotype, anticipates OIS progression. Coherently, FANCD2 overexpression or inhibition of its proteosomal-dependent degradation slightly delays OIS progression. The pro-senescence protease cathepsin L, which activation is anticipated during OIS in FANCD2-depleted cells, also participates to FANCD2 degradation. Our results demonstrate that oncogene activation is first associated with FANCD2 induction and activation, which may support initial cell proliferation, followed by its degradation/downregulation when OIS proceeds.
The effect of Substance P/Heparin conjugated PLCL polymer coating of bioinert ePTFE vascular grafts on the recruitment of both ECs and SMCs for accelerated regeneration
Authors: Kim Donghak , Chung Justin J. , Jung Youngmee , Kim Soo Hyun
Published: November 2019

Artificial vascular grafts consisting of ePTFE have been mainly used in clinics for the treatment of cardiovascular disease. However, artificial grafts can become clogged after a long time due to thrombosis, as graft maturation by endothelialization is limited. The strategy introduced in this study is to induce graft remodeling through interaction between the bioinert graft and the body. The Substance P (SP) and heparin were covalently conjugated with PLCL, an elastic biocompatible copolymer and the Substance P-conjugated PLCL (SP-PLCL) and/or heparin-conjugated PLCL (Hep-PLCL) were vacuum-coated onto ePTFE vascular grafts. To assess the effectiveness of the coating, coated samples were evaluated by implanting them subcutaneously into SD-Rats. Coatings allow grafts to be remodeled by creating a microenvironment where cells can grow by infiltrating into the grafts while also greatly enhancing angiogenesis. In particular, a double coating of Hep-PLCL and SP-PLCL (Hep/SP-PLCL) at four weeks showed markedly improved vascular remodeling through the recruitment of mesenchymal stem cells (MSCs), vascular cells (ECs, SMCs) and M2 macrophages. Based on these results, it is expected that when the Hep/SP-PLCL-coated ePTFE vascular grafts are implantedin situ, long-term patency will be assured due to the appropriate formation of an endothelial layer and smooth muscle cells in the grafts like native vessels.
Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
Authors: Han Kyung Ah , Kim Jinhu , Kim Hyeonho , Kim Dongwook , Lim Dongseok , Ko Jaewon , Um Ji Won
Published: November 2019

Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.
Climate-induced changes in carbon flows across the plant-consumer interface in a small subarctic lake
Authors: Belle Simon , Nilsson Jenny L. , Tõnno Ilmar , Freiberg Rene , Vrede Tobias , Goedkoop Willem
Published: November 2019

Reconstructions of past food web dynamics are necessary for better understanding long-term impacts of climate change on subarctic lakes. We studied elemental and stable isotopic composition of sedimentary organic matter, photosynthetic pigments and carbon stable isotopic composition of Daphnia (Cladocera; Crustacea) resting eggs (δ13CClado) in a sediment record from a small subarctic lake. We examined how regional climate and landscape changes over the last 5800 years affected the relative importance of allochthonous and autochthonous carbon transfer to zooplankton. Overall, δ13CClado values were well in line with the range of theoretical values of aquatic primary producers, confirming that zooplankton consumers in subarctic lakes, even in the long-term perspective, are mainly fuelled by autochthonous primary production. Results also revealed greater incorporations of benthic algae into zooplankton biomass in periods that had a warmer and drier climate and clearer water, whereas a colder and wetter climate and lower water transparency induced higher contributions of planktonic algae to Daphnia biomass. This study thus emphasizes long-term influence of terrestrial-aquatic linkages and in-lake processes on the functioning of subarctic lake food webs.
Reduced-tillage management enhances soil properties and crop yields in a alfalfa-corn rotation: Case study of the Songnen Plain, China
Authors: Chen Jishan , Zhu Ruifen , Zhang Qiang , Kong Xiaolei , Sun Dequan
Published: November 2019

The reduced-tillage (Rt) has been proposed as a strategy to improve soil organic carbon and soil total nitrogen pools. However, little is known of the role of the reduced-tillage compared with the organic (Org) and conventional (Con) management in the Songnen Plain of China. We studied the 4 yr effect of three management strategies (Con, Org and Rt management) on labile soil organic carbon (C) and nitrogen (N) pools, including variation in mineralizable carbon and nitrogen, microbial biomass carbon and nitrogen, dissolved organic carbon and nitrogen in the rotation of alfalfa-corn established in 2009. Soil characteristics including soil organic carbon (SOC), soil total nitrogen (STN), dissolved organic carbon (DOC), dissolved organic nitrogen (DON), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) were quantified in samples collected during the 9 yr rotation of 5yr-alfalfa (Medicago sativa L.) followed by 4 yr corn (Zea mays L.). The mineralizable C was increased in the four years, and although not statistically significant, 12% higher in the fourth year under reduced-tillage than conventional management (268 kg ha−1). Soil organic C was increased by 30% under reduced-tillage compared to conventional management (15.5 Mg ha−1). Three management strategies showed similar labile N pools in the Con and Org management, but differed in the Rt management. Org management showed significantly lesser mineralizable and inorganic N compared to other strategies, but soil microbial community and comparable crop yield across management strategy in year 4, indicating more efficient N use for organic than other management strategy. In our conditions, reduced-tillage for corn cropping after five years of alfalfa grassland can accumulate labile C and N and improve N utilization to for crop yields in the forage-based rotations. These findings suggest an optimal strategy for using Rt management to enhance soil properties and crop yield in plantation soils and provide a new perspective for understanding the potential role of Rt management in plantation soil.
Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis
Authors: Nakano Satoshi , Osaka Shuhei , Sabu Yusuke , Minowa Kei , Hirai Saeko , Kondou Hiroki , Kimura Takeshi , Azuma Yoshihiro , Watanabe Satoshi , Inui Ayano , Bessho Kazuhiko , Nakamura Hidefumi , Kusano Hironori , Nakazawa Atsuko , Tanikawa Ken , Kage Masayoshi , Shimizu Toshiaki , Kusuhara Hiroyuki , Zen Yoh , Suzuki Mitsuyoshi , Hayashi Hisamitsu
Published: November 2019

Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0–3.0;P = 0.003) and 2.4-fold (95% CI, 1.7–3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.
IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice
Authors: Yoshizaki Takamichi , Itoh Satoshi , Yamaguchi Sachiko , Numata Takafumi , Nambu Aya , Kimura Naoyuki , Suto Hajime , Okumura Ko , Sudo Katsuko , Yamaguchi Atsushi , Nakae Susumu
Published: November 2019

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn−/− mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1–, TNF– and IL-17A–dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn−/− mice, suggesting that IL-25 may suppress development of IL-1–, TNF– and IL-17A–dependent aortitis in Il1rn−/− mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25−/−Il1rn−/− mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa—but not Il4 or Il13—in local lesions compared with Il1rn−/− mice. Tissue–, but not immune cell–, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1β and TNF production by IL-25 receptor–expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn−/− mice, contributing to exacerbation of development of IL-1–, TNF– and IL-17A–dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.
Author Correction: A normalized template matching method for improving spike detection in extracellular voltage recordings
Authors: Laboy-Juárez Keven J. , Ahn Seoiyoung , Feldman Daniel E.
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Efficient knockout of phytoene desaturase gene using CRISPR/Cas9 in melon
Authors: Hooghvorst Isidre , López-Cristoffanini Camilo , Nogués Salvador
Published: November 2019

CRISPR/Cas9 system has been widely applied in many plant species to induce mutations in the genome for studying gene function and improving crops. However, to our knowledge, there is no report of CRISPR/Cas9-mediated genome editing in melon (Cucumis melo). In our study, phytoene desaturase gene of melon (CmPDS) was selected as target for the CRISPR/Cas9 system with two designed gRNAs, targeting exons 1 and 2. A construct (pHSE-CmPDS) carrying both gRNAs and the Cas9 protein was delivered by PEG-mediated transformation in protoplasts. Mutations were detected in protoplasts for both gRNAs. Subsequently, Agrobacterium-mediated transformation of cotyledonary explants was carried out, and fully albino and chimeric albino plants were successfully regenerated. A regeneration efficiency of 71% of transformed plants was achieved from cotyledonary explants, a 39% of genetic transformed plants were successful gene edited, and finally, a 42–45% of mutation rate was detected by Sanger analysis. In melon protoplasts and plants most mutations were substitutions (91%), followed by insertions (7%) and deletions (2%). We set up a CRISPR/Cas9-mediated genome editing protocol which is efficient and feasible in melon, generating multi-allelic mutations in both genomic target sites of the CmPDS gene showing an albino phenotype easily detectable after only few weeks after Agrobacterium-mediated transformation.
Virtual Screening of Bio-active Compounds as an Inhibitor of c-FLIP Protein for Cancer Treatment
Authors: Nagaraja Prashantha , Guhathakurta Arighni , Baidya Shweta Sukla , Krishnasamudram Pujitha
Published: November 2019

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is an anti-apoptotic regulatory protein play an important role in cell maintenance and survival to regulate the activation of caspases-8 and -10 proteins in apoptotic signaling pathways. cFLIP mediates death receptors to apoptosis via FAS, TNFR, DR4/DR5, and TNF-related apoptosis-inducing ligand (TRAIL) with the process and activation of procaspase-8 and -10 are over expressed in down process and is the major potential drug targets for cancer therapy. Moreover, abnormal c-FLIP expression has been found in various diseases such as cancer, multiple sclerosis, Alzheimer’s disease, diabetes mellitus, and rheumatoid arthritis. Therefore, c-FLIP-has been identified as potential target for major cancer signaling pathways to inhibit the functions of c-FLIP by targeted therapy. Using computational methods, identified active lead molecules from chemical library databases for the design of potential c-FLIP inhibitors.
Identification of Potential VEGFR2 Inhibitors Employing E-pharmacophore Model, Virtual Screening, Molecular Dynamic Simulation and ADME Analysis
Authors: Rathi E. , Kumar A. , Kini S. G.
Published: November 2019

Angiogenesis is an epochal phenomenon which can be targeted to restrain the growth and metastasis of tumor cells. How to target the angiogenesis? Though Angiogenesis is regulated by multiple molecular mediators, VEGF (vascular endothelial growth factor) is a key mediator of angiogenesis. Hence, targeting of VEGF mediated signal transduction pathway is a pivotal way to suppress angiogenesis in tumor cells. Next question is how to target this signal transduction pathway and what are the promising targets to inhibit this process? Before we will address this question, it is essential to understand that VEGF consist of VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E. Out of all, VEGF-A is a key factor to regulate the angiogenesis phenomenon. However, VEGF-A mediates its biological function through VEGFR-2 (Vascular endothelial growth factor receptor). Hence, VEGFR-2 is the most promising target to suppress angiogenesis in tumor cells.