bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Voltage-Gated Sodium Channel (VGSC) Activity in Human Dorsal Root Ganglion (DRG) Neurons by Herpesvirus Quiescent Infection
Authors: Zhang Qiaojuan , Chen Feng , Martin-Caraballo Miguel , Hsia Shaochung V.
Published: July 2019

The molecular mechanisms of pain associated with alphaherpesvirus latency are not clear. We hypothesize that the voltage-gated sodium channels (VGSC) on dorsal root ganglion (DRG) neurons controlling electrical impulses may have abnormal activity during viral latent infection and reactivation. We used HSV-1 to infect human DRG-derived neuronal cell line HD10.6 to study viral latency establishment, maintenance and reactivation as well as changes of VGSC functional expression. Differentiated cells exhibited robust tetrodotoxin (TTX) sensitive sodium currents and acute infection significantly reduced the VGSC functional expression within 24 hours, and completely abolished the VGSC activity within three days lytic infection. A quiescent state of infection mimicking latency can be achieved by HSV infection in the presence of acyclovir (ACV) for 7 days followed by 5 days of ACV washout and the viruses can remain dormant for another three weeks. It was noted that during HSV-1 latency establishment, the loss of VGSC activity caused by HSV-1 infection could not be blocked by ACV treatment within 3 days infection. However, neurons with continued treatment of ACV for another 4 days showed a gradual recovery of VGSC functional expression. Furthermore, the latent neurons exhibited higher VGSC activity in comparison to controls. The overall regulation of VGSC by HSV-1 during its quiescent infection was proved by increased transcription and possible translation of Nav1.7. Together these observations demonstrated a very complex pattern of electrophysiological changes during HSV infection of DRG neurons, which may have implication for understanding the mechanisms of virus-mediated pain linked to latency and reactivation.

Importance

The reactivation of the herpesvirus from ganglionic neurons may cause cranial nerve disorders and unbearable pain. It is unclear why normal stimuli would trigger enhanced pain sensation in these patients. The current work meticulously studies the functional expression profile changes of VGSC during the process of latency establishment using anin vitromodel. Our results indicated that VGSC activity was eliminated upon infection but steadily recovered during the latency establishment and the latent neurons exhibited even higher VGSC activity. This finding advances our knowledge of how ganglion neurons generated uncharacteristic electrical impulses due to abnormal VGSC functional expression influenced by latent virus.
Assessment of a loop-mediated isothermal amplification (LAMP) assay for the rapid detection of pathogenic bacteria from respiratory samples in patients with hospital-acquired pneumonia
Authors: Vergara Andrea , Boutal Hervé , Ceccato Adrián , López Míriam , Cruells Adrià , Bueno-Freire Leticia , Moreno Javier , de la Bellacasa Jorge Puig , Castro Pedro , Torres Antoni , Marco Francesc , Casals-Pascual Climent , Vila Jordi
Published: July 2019

Introduction

Hospital-acquired pneumonia (HAP) is the one that presents clinically two or more days after admission into the hospital. Rapid identification of the causative agent of HAP will allow an earlier administration of a more appropriate antibiotic therapy and could lead to an improved outcome of patients with HAP.

Methods

First of all, a rapid procedure (< 30 min) to extract the DNA from bronchoalveolar lavage (BAL), endotracheal aspirate (EA) or bronchoaspirate (BAS) was set up. A loop-mediated isothermal amplification reaction (LAMP) specific for Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii was carried out with the extracted solution. The reaction was performed at 65ºC for 30-40 min. LAMP was compared with bacterial culture method.

Results

Overall, 58 positive BAL and 83 EA/BAS samples were tested. The limits of detection varied according to the microorganism detected and to the respiratory sample analyzed. Validation of the LAMP assay with BAL samples showed that the assay was 100% specific and 86.3% sensitive (positive predictive value of 100% and a negative predictive value of 50%). Meanwhile for BAS/EA samples, the assay rendered the following statistical parameters: 100% specificity, 94.6% sensitivity, 100% positive predictive value and 69.2% negative predictive value. These scores were obtained including minor errors as correct. The turnaround time including preparation of the sample and LAMP was circa 1 hour.

Conclusions

LAMP method may be used to detect the most frequent bacteria causing HAP. It is a simple, cheap, sensitive, specific and rapid assay.
Teichoic acids anchor distinct cell wall lamellae in an apically growing bacterium
Authors: Ultee Eveline , van der Aart Lizah T. , van Dissel Dino , Diebolder Christoph A. , van Wezel Gilles P. , Claessen Dennis , Briegel Ariane
Published: July 2019

The bacterial cell wall is a dynamic, multicomponent structure that provides structural support for cell shape and physical protection from the environment. In monoderm species, the thick cell wall is made up predominantly of peptidoglycan, teichoic acids and a variety of capsular glycans. Filamentous monoderm Actinobacteria, such asStreptomyces coelicolor, incorporate new cell wall material at the apex of their hyphal cells during growth. In this study we use cryo-electron tomography to reveal the structural architecture of the cell wall of this bacterium. Our data shows a density difference between the apex and subapical regions of chemically isolated sacculi. Removal of the teichoic acids with hydrofluoric acid reveals a rough and patchy cell wall and distinct lamellae in a number of sacculi. Absence of the extracellular glycans poly-β-1,6-𝒩-acetylglucosamine and a cellulose-like polymer, produced by the MatAB and CslA proteins respectively, results in a thinner sacculus and absence of lamellae and patches. Extracellular glycans might thus form or lead to the formation of the outer cell wall lamella. Based on these findings we propose a revisited model for the complex cell wall architecture of an apically growing bacterium, in which the network of peptidoglycan together with extracellular polymers is structurally supported by teichoic acids.
Generation and quality control of maternal plasma lipidomics data associated with preterm birth
Authors: Mei ZhanLong , Ye Lingfei , Huang Kang , Yang Xi , Chen Xiaomin , Cen Miaolan , Chen Yuan , Zhu Sujun , Zeng Juan , Roy Bhaskar , Jiang Hui , Wang Wen-Jing
Published: July 2019

Preterm birth is not only one of the most common causes of infant deaths but also a great risk for them to have severe subsequent health problems. The causes of preterm birth may be due to a combination of genetic and environmental factors, however, it remains largely unknown. Here we report an untargeted lipidomics dataset of plasma specimens from 258 pregnant women at the stage of twelve to twenty-five gestational weeks. Among them, 44 had extremely to very preterm births, 54 had moderate preterm births, 71 had late preterm births and 89 had full-term deliveries. The metabolomic profiling was generated with an UPLC-MS in both the positive and negative mode, and putative identification of all the metabolites was provided by searching against online databases. The quality assessment performed on quality control samples showed that the data is reproducible, robust and reliable. Both the raw data files, the raw and processed data matrix were available on MetaboLights, which may be used as a valuable validation dataset for new findings and a test dataset for novel algorithms.
Comparative transcriptomics reveal that adaptive evolution in immune genes drives the local adaptation and speciation of schizothoracine fish
Authors: Qi Delin , Wu Rongrong , Chao Yan , Xia Mingzhe , Chen Qichang , Zheng Zhiqin
Published: July 2019

Transcriptomic information can increase our understanding of the molecular processes underlying speciation. The schizothoracine fish, the largest and most diverse taxon within the Qinghai-Tibetan Plateau (QTP) ichthyofauna, are widespread in drainages throughout the QTP. These fish thus serve as an ideal model group with which to investigate how molecular evolution drives local adaptation during speciation. Here, we performed an interspecific comparative analysis of the transcriptomes of 13 schizothoracine fish species, and identified the key positively selected genes (PSGs) associated with significantly enriched functions and metabolite pathway acting on the specific lineages (or species) in the schizothoracine fish. We generated 64,637,602–83,968,472 sequence reads per schizothoracine fish species using Illumina sequencing, yielding 95,251–145,805 unigenes per species. We identified 52 out of 2,064 orthologous genes as candidate genes, which have probably been subject to positive selection along the whole schizothoracine fish lineage. Nine of these candidate genes were significantly enriched in key GO functions and metabolite pathways, all of which were associated with the immune system. The lineage-specific evolution test showed species-specific differences among the nine candidate PSGs, probably due to ecological differences among drainages, as well as among micro-habitats in the same drainage (e.g., benthic and pelagic). Here, we provide evidence that the adaptive evolution of immune genes, along with the uplift of the QTP, allowed new schizothoracine species to colonize ecologically novel environments or to exploit vacant ecological niches during speciation.

Supplemental material available at FigShare: https://doi.org/10.25387/.
Sensory-modality independent activation of the brain network for language
Authors: Arana Sophie , Marquand André , Hultén Annika , Hagoort Peter , Schoffelen Jan-Mathijs
Published: July 2019

The meaning of a sentence can be understood, whether presented in written or spoken form. Therefore it is highly probable that brain processes supporting language comprehension are at least partly independent of sensory modality. To identify where and when in the brain language processing is independent of sensory modality, we directly compared neuromagnetic brain signals of 200 human subjects (102 males) either reading or listening to sentences. We used multiset canonical correlation analysis to align individual subject data in a way that boosts those aspects of the signal that are common to all, allowing us to capture word-by-word signal variations, consistent across subjects and at a fine temporal scale. Quantifying this consistency in activation across both reading and listening tasks revealed a mostly left hemispheric cortical network. Areas showing consistent activity patterns include not only areas previously implicated in higher-level language processing, such as left prefrontal, superior & middle temporal areas and anterior temporal lobe, but also parts of the control-network as well as subcentral and more posterior temporal-parietal areas. Activity in this supramodal sentence processing network starts in temporal areas and rapidly spreads to the other regions involved. The findings do not only indicate the involvement of a large network of brain areas in supramodal language processing, but also indicate that the linguistic information contained in the unfolding sentences modulates brain activity in a word-specific manner across subjects.
Autophagy dark genes: Can we find them with machine learning?
Authors: Oprea Tudor I. , Yang Jeremy J. , Byrd Daniel R. , Deretic Vojo
Published: July 2019

Identifying novel genes associated with autophagy (ATG) in man remains an important task for gaining complete understanding on this fundamental physiological process. A machine-learning guided approach can highlight potentially “missing pieces” linking core autophagy genes with understudied, “dark” genes that can help us gain deeper insight into these processes. In this study, we used a set of 103 (out of 288 genes from the Autophagy Database, ATGdb), based on the presence of ATG-associated terms annotated from 3 secondary sources: GO (gene ontology), KEGG pathway and UniProt keywords, respectively. We regarded these as additional confirmation for their importance in ATG. As negative labels, we used the OMIM list of genes associated with monogenic diseases (after excluding the 288 ATG-associated genes). Data associated with these genes from 17 different public sources were compiled and used to derive a Meta Path/XGBoost (MPxgb) machine learning model trained to distinguish ATG and non-ATG genes (10-fold cross-validated, 100-times randomized models, median AUC = 0.994 +/− 0.0084). Sixteen ATG-relevant variables explain 64% of the total model gain, and 23% of the top 251 predicted genes are annotated in ATGdb. Another 15 genes have potential ATG associations, whereas 193 do not. We suggest that some of these 193 genes may represent “autophagy dark genes”, and argue that machine learning can be used to guide autophagy research in order to gain a more complete functional and pathway annotation of this complex process.
Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells
Authors: Hühn Daniela , Martí-Rodrigo Pablo , Mouron Silvana , Hansel Catherine S. , Tschapalda Kirsten , Porebski Bartlomiej , Häggblad Maria , Lidemalm Louise , Quintela-Fandino Miguel A. , Carreras-Puigvert Jordi , Fernandez-Capetillo Oscar
Published: July 2019

Estrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ERα depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.
Endocytic Clathrin Coats Develop Curvature at Early Stages of Their Formation
Authors: Willy Nathan M. , Ferguson Joshua P. , Silahli Salih , Cakez Cemal , Hasan Farah , Chen Yan , Wu Min , Chang Henry C. , Travesset Alex , Li Siyu , Zandi Roya , Li Dong , Betzig Eric , Cocucci Emanuele , Kural Comert
Published: July 2019

Sculpting a flat patch of membrane into an endocytic vesicle requires curvature generation on the cell surface, which is the primary function of endocytic protein complexes. The mechanism through which membrane curvature is imposed during formation of clathrin-coated vesicles is an ongoing controversy. Using super-resolved live cell fluorescence imaging, we demonstrate that curvature generation by clathrin-coated pits can be detected in real time within cultured cells and tissues of developing metazoan organisms. We found that the footprint of clathrin coats increase monotonically during formation of curved pits at different levels of plasma membrane tension. Our findings are only compatible with models that predict curvature generation at early stages of endocytic clathrin-coated pit formation. Therefore, clathrin-coated vesicle formation does not necessitate a dynamically unstable clathrin lattice that would allow an abrupt flat-to-curved transition.

Endocytic clathrin coats acquire curvature without a flat-to-curved transition that requires an extensive reorganization of the clathrin lattice.
EEG and fMRI Evidence for Autobiographical Memory Reactivation in Empathy
Authors: Meconi Federica , Linde-Domingo Juan , Ferreira Catarina S. , Michelmann Sebastian , Staresina Bernhard , Apperly Ian , Hanslmayr Simon
Published: July 2019

Empathy relies on the ability to mirror and to explicitly infer others’ inner states. Theoretical accounts suggest that memories play a role in empathy but direct evidence of a reactivation of autobiographical memories (AM) in empathy is yet to be shown. We addressed this question in two experiments. In experiment 1, electrophysiological activity (EEG) was recorded from 28 participants who performed an empathy task in which targets for empathy were depicted in contexts for which participants either did or did not have an AM, followed by a task that explicitly required memory retrieval of the AM and non-AM contexts. The retrieval task was implemented to extract the neural fingerprints of AM and non-AM contexts, which were then used to probe data from the empathy task. An EEG pattern classifier was trained and tested across tasks and showed evidence for AM reactivation when participants were preparing their judgement in the empathy task. Participants self-reported higher empathy for people depicted in situations they had experienced themselves as compared to situations they had not experienced. A second independent fMRI experiment replicated this behavioural finding and showed the predicted activation in the brain networks underlying both AM retrieval and empathy: precuneus, posterior parietal cortex, superior and inferior parietal lobule and superior frontal gyrus. Together, our study reports behavioural, electrophysiological and fMRI evidence that robustly supports the involvement of AM reactivation in empathy.
Insights into actin polymerization and nucleation using a coarse grained model
Authors: Horan Brandon G. , Hall Aaron R. , Vavylonis Dimitrios
Published: July 2019

We studied actin filament polymerization and nucleation with molecular dynamics simulations and a previously established coarse-grained model having each residue represented by a single interaction site located at the Cαatom. We approximate each actin protein as a fully or partially rigid unit to identify the equilibrium structural ensemble of interprotein complexes. Monomers in the F-actin configuration bound to both barbed and pointed ends of a short F-actin filament at the anticipated locations for polymerization. Binding at both ends occurred with similar affinity. Contacts between residues of the incoming subunit and the short filament were consistent with expectation from models based on crystallography, X-ray diffraction and cryo-electron microscopy. Binding at the barbed and pointed end also occurred at an angle with respect to the polymerizable bound structure, and the angle range depended on the flexibility of the D-loop. Additional barbed end bound states were seen when the incoming subunit was in the G-actin form. Consistent with an activation barrier for pointed end polymerization, G-actin did not bind at an F-actin pointed end. In all cases, binding at the barbed end also occurred in a configuration similar to the antiparallel (lower) dimer. Individual monomers bound each other in a short-pitch helix complex in addition to other configurations, with several of them apparently non-productive for polymerization. Simulations with multiple monomers in the F-actin form show assembly into filaments as well as transient aggregates at the barbed end. We discuss the implications of these observations on the kinetic pathway of actin filament nucleation and polymerization and possibilities for future improvements of the coarse-grained model.

SIGNIFICANCE

Control of actin filament nucleation and elongation has crucial importance to cellular life. We show that coarse-grained molecular dynamics simulations are a powerful tool which can gauge involved mechanisms at reasonable computational cost, while retaining essential features of the fully atomic, yet less computationally tractable, system. Using a knowledge-based potential demonstrates the power of these methods for explaining and reproducing polymerization. Intermediate actin complexes identified in the simulations may play critical roles in the kinetic pathways of actin polymerization which may have been difficult to observe in prior experiments. These methods have been sparsely applied to the actin system, yet have potential to answer many important questions in the field.
A cortex-specific PBP contributes to cephalosporin resistance in Clostridium difficile
Authors: Alabdali Yasir Adil Jabbar , Oatley Peter , Kirk Joseph A. , Fagan Robert P.
Published: July 2019

Sporulation is a complex cell differentiation programme shared by many members of the Firmicutes, the end result of which is a highly resistant, metabolically inert spore that can survive harsh environmental insults. Clostridium difficile spores are essential for transmission of disease and are also required for recurrent infection. However, the molecular basis of sporulation is poorly understood, despite parallels with the well-studied Bacillus subtilis system. The spore envelope consists of multiple protective layers, one which is a specialised layer of peptidoglycan, called the cortex, that is essential for the resistant properties of the spore. We have identified and characterised a penicillin binding protein (PBP) that is required for cortex synthesis in C. difficile. Surprisingly this PBP was also found to contribute to cephalosporin resistance, indicating an additional role in the synthesis of vegetative cell wall. This is the first description of a cortex-specific PBP in C. difficile and begins the process of unravelling cortex biogenesis in this important pathogen.
Attractor-state itinerancy in neural circuits with synaptic depression
Authors: Chen Bolun , Miller Paul
Published: July 2019

Neural populations with strong excitatory recurrent connections can support bistable states in their mean firing rates. Multiple fixed points in a network of such bistable units can be used to model memory retrieval and pattern separation. The stability of fixed points may change on a slower timescale than that of the dynamics due to short-term synaptic depression, leading to transitions between quasi-stable point attractor states in a sequence that depends on the history of stimuli. To better understand these behaviors, we study a minimal model, which characterizes multiple fixed points and transitions between them in response to stimuli with diverse time- and amplitude-dependences. The interplay between the fast dynamics of firing rate and synaptic responses and the slower timescale of synaptic depression makes the neural activity sensitive to the amplitude and duration of square-pulse stimuli in a non-trivial, history-dependent manner. Weak cross-couplings further deform the basins of attraction for different fixed points into intricate shapes. Our analysis provides a natural explanation for the system’s rich responses to stimuli of different durations and amplitudes while demonstrating the encoding capability of bistable neural populations for dynamical features of incoming stimuli.
Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling
Authors: Connor David A , Wittenberg Ruthie E , Drogin Jillian , Mak Allison , Dani John A
Published: July 2019

Alcohol use disorders (AUDs) continue to be a significant public health problem. Early life stress and adversity have long-lasting effects on a wide range of behaviors, including responses to drugs of abuse. Epidemiological evidence indicates that exposure to early life stress contributes to alcohol use disorders and, while it is known that stress and alcohol both act on overlapping mesolimbic circuitry, the cellular mechanisms underlying the relationship between stress and alcohol intake are not well understood. Previous work has demonstrated that acute stress increases ethanol intake mediated by changes in GABA signaling within the ventral tegmental area (VTA). Here we investigated if adolescent stress exposure might elicit long-term, persistent increases in ethanol self-administration associated with altered VTA GABA signaling. To this end, we exposed adolescent postnatal day (PND) 28 male rats to 14 days of chronic variable stress (CVS) and then examined operant ethanol self-administration begun at least 30 days later. We found that adolescent stress exposure resulted in significantly increased ethanol self-administration in adulthood. In contrast, adult (PND 82) male rats exposed to the same CVS protocol did not display increased ethanol self-administration that was begun 30 days later. Furthermore, we found that adolescent stress exposure resulted in enhancement of ethanol-induced GABA signaling onto VTA dopamine neurons and impairments in VTA GABA chloride homeostasis. The results indicate that adolescence is a period vulnerable to stress, which produces long-term changes in VTA GABA signaling associated with increased ethanol self-administration behavior.
Efficientde novoassembly of eleven human genomes using PromethION sequencing and a novel nanopore toolkit
Authors: Shafin Kishwar , Pesout Trevor , Lorig-Roach Ryan , Haukness Marina , Olsen Hugh E. , Bosworth Colleen , Armstrong Joel , Tigyi Kristof , Maurer Nicholas , Koren Sergey , Sedlazeck Fritz J. , Marschall Tobias , Mayes Simon , Costa Vania , Zook Justin M. , Liu Kelvin J. , Kilburn Duncan , Sorensen Melanie , Munson Katy M. , Vollger Mitchell R. , Eichler Evan E. , Salama Sofie , Haussler David , Green Richard E. , Akeson Mark , Phillippy Adam , Miga Karen H. , Carnevali Paolo , Jain Miten , Paten Benedict
Published: July 2019

Present workflows for producing human genome assemblies from long-read technologies have cost and production time bottlenecks that prohibit efficient scaling to large cohorts. We demonstrate an optimized PromethION nanopore sequencing method for eleven human genomes. The sequencing, performed on one machine in nine days, achieved an average 63x coverage, 42 Kb read N50, 90% median read identity and 6.5x coverage in 100 Kb+ reads using just three flow cells per sample. To assemble these data we introduce new computational tools: Shasta - ade novolong read assembler, and MarginPolish & HELEN - a suite of nanopore assembly polishing algorithms. On a single commercial compute node Shasta can produce a complete human genome assembly in under six hours, and MarginPolish & HELEN can polish the result in just over a day, achieving 99.9% identity (QV30) for haploid samples from nanopore reads alone. We evaluate assembly performance for diploid, haploid and trio-binned human samples in terms of accuracy, cost, and time and demonstrate improvements relative to current state-of-the-art methods in all areas. We further show that addition of proximity ligation (Hi-C) sequencing yields near chromosome-level scaffolds for all eleven genomes.
PsyMuKB: A De Novo Variant Knowledge Base Integrating Transcriptional and Translational Information to Identify Isoform-specific Mutations in Developmental Disorders
Authors: Lin Guan Ning , Guo Sijia , Tan Xian , Wang Weidi , Qian Wei , Song Weichen , Wang Jingru , Yu Shunying , Wang Zhen , Cui Donghong , Wang Han
Published: July 2019

De novo variants (DNVs) are one of the most significant contributors to severe early-onset genetic disorders such as autism spectrum disorder, intellectual disability, and other developmental and neuropsychiatric (DNP) disorders. Currently, a plethora of DNVs have being identified through the use of next-generation sequencing and much effort has been made to understand their impact at the gene level; however, there has been little exploration of the impact at the isoform level. The brain contains a high level of alternative splicing and regulation, and exhibits a more divergent splicing program than other tissues; therefore, it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders. To facilitate better usage and improve the isoform-level interpretation of variants, we developed the PsyMuKB (NeuroPsychiatric Mutation Knowledge Base), a knowledge base containing a comprehensive, carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoform-specific mutations. PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations, such as expression, transcript genomic structures, protein interactions, and the mutation sites mapped on the protein structures. It also provides an easy-to-use web interface, allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms. PsyMuKB thus constitutes a valuable resource for identifying tissue-specific de novo mutations for further functional studies of related disorders. PsyMuKB is freely accessible at http://psymukb.net.
Soil chloride content influences the response of bacterial but not fungal diversity to silver nanoparticles entering soil via wastewater treatment processing
Authors: Forstner Christian , Orton Thomas G. , Wang Peng , Kopittke Peter M. , Dennis Paul G.
Published: July 2019

Silver nanoparticles (NPs) are among the most widely used nanomaterials and are entering soil ecosystems, mainly via biosolids in agriculture. When added directly to soils, metallic Ag-NPs have been shown to affect microbial communities, which underpin important ecosystem functions. During wastewater treatment processing, metallic Ag-NPs are rapidly converted to Ag2S, which is relatively insoluble and less toxic. Furthermore, recent evidence indicates that silver bioavailability is influenced by soil chloride content. Hence there is a need to understand the impacts of wastewater treatment processed Ag-NPs at varying levels of salinity on soil microbial diversity. In this study, we examined how the application of 0 g, 1 g and 2 g kg−1 NaCl to soil influence the effects of 0 mg, 1 mg and 10 mg kg−1 Ag, applied as wastewater treatment processed Ag-NPs, on bacterial and fungal diversity over time. Using high-throughput phylogenetic marker gene sequencing we demonstrate that, despite being theoretically less toxic, wastewater treatment processed Ag-NPs can affect the composition of soil bacterial and fungal communities, and influence bacterial alpha diversity. In addition, we found that silver-associated changes in bacterial community composition were affected by soil chloride content, with more acute responses to silver being observed in more saline soils. This work highlights that the release of Ag-NPs into soils via realistic exposure pathways can alter microbial diversity and that these effects may be influenced by soil chloride content.

Summary capsule

Soil chloride content influences the response of bacterial but not fungal diversity to wastewater treatment processed silver nanoparticles.
Alteration of cardiolipin-dependent mitochondrial coupling in muscle protects against obesity
Authors: Prola Alexandre , Blondelle Jordan , Vandestienne Aymeline , Piquereau Jérôme , Denis Raphaël GP , Guyot Stéphane , Chauvin Hadrien , Mourier Arnaud , Letheule Martine , Maurer Marie , Henry Céline , Khadhraoui Nahed , Courtin Guillaume , Blanchard-Gutton Nicolas , Guillaud Laurent , Barthélémy Inès , Gressette Mélanie , Solgadi Audrey , Dumont Florent , Castel Julien , Ternacle Julien , Demarquoy Jean , Malgoyre Alexandra , Koulmann Nathalie , Derumeaux Geneviève , Giraud Marie-France , Blot Stéphane , Joubert Frédéric , Veksler Vladimir , Luquet Serge , Relaix Frédéric , Tiret Laurent , Pilot-Storck Fanny
Published: July 2019

The tubular shape of mitochondrial cristae depends upon a specific composition of the inner mitochondrial membrane, including cardiolipin that allows strong curvature and promotes optimal organization of ATP synthase. Here we identifyHacd1,which encodes an enzyme involved in very long chain fatty acid biosynthesis, as a key regulator of composition, structure and functional properties of mitochondrial membranes in muscle. InHacd1-deficient mice, the reduced cardiolipin content was associated with dilation of cristae and caused defective phosphorylating respiration, characterized by absence of proton leak and oxidative stress.

The skeletal muscle-specific mitochondrial coupling defect produced a global elevation in basal energy expenditure with increased carbohydrate and lipid catabolism, despite decreased muscle mass and locomotor capacities. Mice were protected against diet-induced obesity despite reduced muscle activity, providing anin vivoproof of concept that reducing mitochondrial coupling efficiency in skeletal muscle might be an actionable mechanism in metabolic disease conditions.
Biological Plasticity Rescues Target Activity in CRISPR Knockouts
Authors: Smits Arne H. , Ziebell Frederik , Joberty Gerard , Zinn Nico , Mueller William F. , Clauder-Münster Sandra , Eberhard Dirk , Savitski Maria Fälth , Grandi Paola , Jakob Petra , Michon Anne-Marie , Sun Hanice , Tessmer Karen , Bürckstümmer Tilmann , Bantscheff Marcus , Steinmetz Lars M. , Drewes Gerard , Huber Wolfgang
Published: July 2019

Gene knockouts (KOs) are efficiently engineered through CRISPR-Cas9-induced frameshift mutations. While DNA editing efficiency is readily verified by DNA sequencing, a systematic understanding of the efficiency of protein elimination has been lacking. Here, we devised an experimental strategy combining RNA-seq and triple-stage mass spectrometry (SPS-MS3) to characterize 193 genetically verified deletions targeting 136 distinct genes generated by CRISPR-induced frameshifts in HAP1 cells. We observed residual protein expression for about one third of the quantified targets, at variable levels from low to original, and identified two causal mechanisms, translation reinitiation leading to N-terminally truncated target proteins, or skipping of the edited exon leading to protein isoforms with internal sequence deletions. Detailed analysis of three truncated targets, BRD4, DNMT1 and NGLY1, revealed partial preservation of protein function. Our results imply that systematic characterization of residual protein expression or function in CRISPR-Cas9 generated KO lines is necessary for phenotype interpretation.
Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture
Authors: Tadele Markos , Abay Solomon M. , Makonnen Eyasu , Hailu Asrat
Published: July 2019

Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given low attention in drug discovery researches to narrow the existing gap in safety and efficacy of the currently used drugs to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Aiming to look for potential anti-leishmanial hits and leads, we screened MMV Pathogen Box against clinically isolated L. donovani strain. Compounds were screened against promastigote, and then against amastigote stages; of which, 35 compounds showed >50% inhibition on promastigotes in the initial screen (1 μM). Out of these compounds, 9 compounds showed >70% inhibition with median inhibitory concentration (IC50) ranges from 12 nM to 491 nM on anti-promastigote assay and 53 to 704 nM on intracellular amastigote assay. Identified compounds demonstrated good safety on THP-1 cell lines and sheep RBCs, and appropriate physico-chemical property suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as lead compounds. Among these compounds, anti-tubercular agent MMV688262 (delamanid) showed synergistic effect with amphotericin B, indicating the prospect of this compound for combination therapy. The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure activity relationship studies. Future works also needs to investigate antiamastigotes activity of remaining ‘hits’, which were not covered in the present study.

Authors summary

Visceral leishmaniasis is a major public health problem in endemic regions. Different drugs have been used to treat visceral leishmaniasis. However, the available drugs are either toxic, non-compliance to the patient, painful upon administration, low in efficacy, or costly. New chemical entities that overcome the limitations of existing drugs are therefore desperately needed. Screening of 400 pathogen box compounds against of Leishmania donovani clinical isolate resulted in identification of 35 compounds with >50% inhibition against promastigotes at 1 μM. Out of these compounds, 9 showed >70% inhibition with median inhibitory concentration ranges from 12 nM to 491 nM on anti-promastigote assay, and 53 to 704 nM on intracellular amastigote assay. Our work identified new compounds which hold promise for further drug development.
TDP-43 regulates the expression levels of Disc-large in skeletal muscles to promote the assemble of the neuromuscular synapses in Drosophila
Authors: Strah Nina , Romano Giulia , Introna Clelia , Klima Raffaella , Megighian Aram , Nizzardo Monica , Feiguin Fabian
Published: July 2019

Background

Alterations in the intracellular distribution of TDP-43 were observed in the skeletal muscles of patients suffering from ALS. However, it is not clear whether these modifications play an active role in the disease or represent a physiological adaptation to muscles homeostasis.

Result

To answer these questions, we modulated the activity of this protein in Drosophila muscles and observed that TDP-43 was required in these tissues to promote the formation and growth of the neuromuscular synapses. Moreover, we identified that TDP-43 regulates the expression levels of Disc-large (Dlg) and demonstrated that the modulation of Dlg activity, in skeletal muscles or motoneurons, was sufficient to recover the TDP-43-null locomotive and synaptic defects in flies. Additionally, we found that similar mechanisms are conserved in human cell lines and present in tissues derived from ALS patients.

Conclusions

Our results uncover the physiological role of TDP-43 in skeletal muscles as well as the mechanisms behind the autonomous and non-autonomous behavior of this protein in the organization of the neuromuscular synapses.
Crystal structures of two isomeric 2-aryl-3-phenyl-1,3-thiazepan-4-ones
Authors: Yennawar Hemant P. , Peterson Samuel D. , Silverberg Lee J.
Published: July 2019

The crystal of 6-(3-nitrophenyl)-7-phenyl-5-thia-7-azaspiro[2.6]nonan-8-one (1), C19H18N2O3S, has monoclinic (P21/n) symmetry while that of its isomer 6-(4-nitrophenyl)-7-phenyl-5-thia-7-azaspiro[2.6]nonan-8-one (2), has orthorhombic (Pca21) symmetry: compound 1 has two molecules, A and B, in the asymmetric unit while 2 has one. In all three molecules, the seven-membered thiazepan ring exhibits a chair conformation with Q2 and Q3 values (Å) of 0.521 (3), 0.735 (3) and 0.485 (3), 0.749 (3) in 1 and 0.517 (5), 0.699 (5) in 2. In each structure, the phenyl rings attached to adjacent atoms of the thiazepan ring have interplanar angles ranging between 41 and 47°. Except for the nitro groups, the three molecules have similar conformations when overlayed in pairs. Both crystal structures are consolidated by C—H...O hydrogen bonds.
Six 1-aroyl-4-(4-methoxyphenyl)piperazines: similar molecular structures but different patterns of supramolecular assembly
Authors: Kiran Kumar Haruvegowda , Yathirajan Hemmige S. , Sagar Belakavadi K. , Foro Sabine , Glidewell Christopher
Published: July 2019

Six new 1-aroyl-4-(4-methoxyphenyl)piperazines have been prepared, using coupling reactions between benzoic acids and N-(4-methoxyphenyl)piperazine. There are no significant hydrogen bonds in the structure of 1-benzoyl-4-(4-methoxyphenyl)piperazine, C18H20N2O2, (I). The molecules of 1-(2-fluorobenzoyl)-4-(4-methoxyphenyl)piperazine, C18H19FN2O2, (II), are linked by two C—H...O hydrogen bonds to form chains of rings, which are linked into sheets by an aromatic π–π stacking interaction. 1-(2-Chlorobenzoyl)-4-(4-methoxyphenyl)piperazine, C18H19ClN2O2, (III), 1-(2-bromobenzoyl)-4-(4-methoxyphenyl)piperazine, C18H19BrN2O2, (IV), and 1-(2-iodobenzoyl)-4-(4-methoxyphenyl)piperazine, C18H19IN2O2, (V), are isomorphous, but in (III) the aroyl ring is disordered over two sets of atomic sites having occupancies of 0.942 (2) and 0.058 (2). In each of (III)–(V), a combination of two C—H...π(arene) hydrogen bonds links the molecules into sheets. A single O—H...O hydrogen bond links the molecules of 1-(2-hydroxybenzoyl)-4-(4-methoxyphenyl)piperazine, C18H20N2O3, (VI), into simple chains. Comparisons are made with the structures of some related compounds.
The impact paths of social capital and the effects of microfinance
Authors: Xiong Fang , You Jia Lu
Published: July 2019

Purpose

The purpose of this paper is to investigate the impact paths of the social capital and the effects of microfinance in rural China, and address effective methods to enhance the effects of microfinance for rural China.

Design/methodology/approach

Using a structural equation model with survey data from 350 rural households in China, this paper analyzes empirically whether greater level of social sanctions and social relations caused more tangible effects of microfinance, and whether tangible effects of microfinance are associated with social capital formation of households.

Findings

The results indicate that social capital promotes the effects of microfinance and the process of providing microfinance service is also the process of building social capital. Moreover, social sanctions diminish the effects of microfinance while social relations boost them and enhance the effects of microfinance that can encourage social capital formation. Results also show that a reverse causal relationship exists between social sanctions and social relations.

Research limitations/implications

The empirical results imply that actively utilizing and creating social capital is vital to improve the effects of microfinance, and microfinance institutions (MFIs) should concentrate more on harmonious social relations and deliberately build social capital.

Practical implications

These findings imply that actively utilizing and creating social capital is vital to improve the effects of microfinance, and the MFIs should concentrate more on harmonious social relations and deliberately build social capital to enhance the effects of microfinance while prudently use social sanctions.

Social implications

Enhancing the effects of microfinance, while prudently using social sanctions, increases households income.

Originality/value

This paper originates to investigate the links between the social capital and the effects of microfinance in a mutual way, and the results urge more attentions on the harmonious social relations which have been ignored to enhance the effects of microfinance.
SOM approach for clustering customers using credit card transactions
Authors: Yanık Seda , Elmorsy Abdelrahman
Published: July 2019

Purpose

The purpose of this paper is to generate customer clusters using self-organizing map (SOM) approach, a machine learning technique with a big data set of credit card consumptions. The authors aim to use the consumption patterns of the customers in a period of three months deducted from the credit card transactions, specifically the consumption categories (e.g. food, entertainment, etc.).

Design/methodology/approach

The authors use a big data set of almost 40,000 credit card transactions to cluster customers. To deal with the size of the data set and the eliminated the required parametric assumptions the authors use a machine learning technique, SOMs. The variables used are grouped into three as demographical variables, categorical consumption variables and summary consumption variables. The variables are first converted to factors using principal component analysis. Then, the number of clusters is specified by k-means clustering trials. Then, clustering with SOM is conducted by only including the demographical variables and all variables. Then, a comparison is made and the significance of the variables is examined by analysis of variance.

Findings

The appropriate number of clusters is found to be 8 using k-means clusters. Then, the differences in categorical consumption levels are investigated between the clusters. However, they have been found to be insignificant, whereas the summary consumption variables are found to be significant between the clusters, as well as the demographical variables.

Originality/value

The originality of the study is to incorporate the credit card consumption variables of customers to cluster the bank customers. The authors use a big data set and dealt with it with a machine learning technique to deduct the consumption patterns to generate the clusters. Credit card transactions generate a vast amount of data to deduce valuable information. It is mainly used to detect fraud in the literature. To the best of the authors’ knowledge, consumption patterns obtained from credit card transaction are first used for clustering the customers in this study.
Making the student voice count: using qualitative student feedback to enhance the student experience
Authors: Shah Mahsood , Pabel Anja
Published: July 2019

Purpose

The purpose of this paper is to outline how qualitative data can be used to gain insights into the experience of different cohorts of students including online and on-campus students.

Design/methodology/approach

Qualitative data from student surveys are used to analyse three years of data. The text analytics software Leximancer was used to analyse the qualitative student comments.

Findings

Comparing comments of on-campus and online students, the findings indicate that the students had different perceptions in regards to what they rated as best aspects of their course and what needed improvement.

Originality/value

The study is based on three years of qualitative comments collected in student surveys. The study is unique, given that previous studies have looked at qualitative comments in general rather than comparing the experience of online and on-campus students.
Exploring service quality and its customer consequences in the sports spectating sector
Authors: Koronios Konstantinos , Kriemadis Athanasios , Papadopoulos Andreas
Published: July 2019

Purpose

The purpose of this paper is to investigate issues relevant to service quality and propose a conceptual model addressing the convictions held by consumers in relation to the service quality of sport services as regards spectators and their influence on sport consumption.

Design/methodology/approach

A quantitative method was used for the purpose of this study and 1,643 questionnaires were gathered and analyzed. The current research intended to employ an integrated service quality model within the scope of sport spectating. The model included five fundamental factors and they were examined in association with the behavioral intentions that spectators have. By combining all these factors and aspects, it was attempted to shape consumers’ general perception regarding quality in service. The model of the research considers quality in service to be a hierarchical construct comprising many dimensions and it is observed that service quality can be classified into five factors, all of which can be defined by a variety of corresponding sub-factors.

Findings

The outcomes showed that four of the suggested factors regarding quality (i.e. game quality, augmented service quality, interaction quality and outcome quality) had an important as well as favorable influence on sport consumption.

Research limitations/implications

The empirical evidence for this research is derived from one specific professional sport event (European Basketball League) and spectators who took part were from Greece. Future research could use a wider sample of sport events and the participation of spectators from various countries is necessary before such findings are generalized.

Originality/value

The present research provides a contemporary analysis of factors influencing sport spectators anticipated quality and their influence on sport consumption.