bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy inBRCA1/2-mutant metastatic breast cancer
Authors: Waks Adrienne G. , Cohen Ofir , Kochupurakkal Bose , Kim Dewey , Dunn Connor E. , Buendia Buendia Jorge , Wander Seth , Helvie Karla , Lloyd Maxwell R. , Marini Lori , Hughes Melissa E. , Freeman Samuel S. , Percy Ivy S. , Geradts Joseph , Isakoff Steve , LoRusso Patricia , Adalsteinsson Viktor A. , Tolaney Sara M. , Matulonis Ursula , Krop Ian E. , D’Andrea Alan D. , Winer Eric P. , Lin Nancy U. , Shapiro Geoffrey I. , Wagle Nikhil
Published: November 2019

Background

Little is known about mechanisms of resistance to PARP inhibitors and platinum chemotherapy in patients with metastatic breast cancer andBRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure.

Patients and Methods

We obtained tumor biopsies from metastatic breast cancer patients withBRCA1/2deficiency before and after acquired resistance to PARP inhibitor or platinum chemotherapy. Whole exome sequencing was performed on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was performed for functional assessment of intact homologous recombination.

Results

Pre- and post-resistance tumor samples were sequenced from 8 patients (4 withBRCA1and 4 withBRCA2mutation; 4 treated with PARP inhibitor and 4 with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germlineBRCA1deficiency acquired genomic alterations anticipated to restore homologous recombination through increased DNA end resection: loss ofTP53BP1in one patient and amplification ofMRE11Ain another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of homologous recombination. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy.

Conclusions

Genomic reversion inBRCA1/2was the most commonly observed mechanism of resistance, occurring in 4 of 8 patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.
Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer
Authors: Pennycuick Adam , Teixeira Vitor H. , AbdulJabbar Khalid , Ahmed Raza Shan E , Lund Tom , Akarca Ayse , Rosenthal Rachel , Pipinikas Christodoulos P. , Lee-Six Henry , Chandrasekharan Deepak P. , Hynds Robert E. , Gowers Kate H. C. , Henry Jake Y. , Denais Celine , Falzon Mary , Antoniou Sophia , Durrenberger Pascal F. , Furness Andrew , Carroll Bernadette , Thakrar Ricky M. , George Philip J. , Marafioti Teresa , Swanton Charles , Thirlwell Christina , Campbell Peter J. , Yuan Yinyin , Quezada Sergio A. , McGranahan Nicholas , Janes Sam M.
Published: November 2019

Before squamous cell lung cancer develops, pre-cancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. While recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of pre-cancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in-situ lesions harbour more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, TGF-beta signalling is overactive, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the CIS lesions as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. This study identifies mechanisms by which pre-cancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early stage lung cancer.
A framework for closed-loop neurofeedback for real-time EEG decoding
Authors: Tuckute Greta , Hansen Sofie Therese , Kjaer Troels Wesenberg , Hansen Lars Kai
Published: November 2019

Neurofeedback based on real-time brain imaging allows for targeted training of brain activity with demonstrated clinical applications. A rapid technical development of electroen-cephalography (EEG)-based systems and an increasing interest in cognitive training has lead to a call for accessible and adaptable software frameworks. Here, we present and outline the core components of a novel open-source neurofeedback framework based on scalp EEG signals for real-time neuroimaging, state classification and closed-loop feedback.

The software framework includes real-time signal preprocessing, adaptive artifact rejection, and cognitive state classification from scalp EEG. The framework is implemented using exclusively Python source code to allow for diverse functionality, high modularity, and easy extendibility of software development depending on the experimenter’s needs.

As a proof of concept, we demonstrate the functionality of our new software framework by implementing an attention training paradigm using a consumer-grade, dry-electrode EEG system. Twenty-two participants were trained on a single neurofeedback session with behavioral pre- and post-training sessions within three consecutive days. We demonstrate a mean decoding error rate of 34.3% (chance=50%) of subjective attentional states. Hence, cognitive states were decoded in real-time by continuously updating classification models on recently recorded EEG data without the need for any EEG recordings prior to the neurofeedback session.

The proposed software framework allows a wide range of users to actively engage in the development of novel neurofeedback tools to accelerate improvements in neurofeedback as a translational and therapeutic tool.
Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages
Authors: Dupont Maeva , Souriant Shanti , Balboa Luciana , Vu Manh Thien-Phong , Pingris Karine , Rousset Stella , Cougoule Céline , Rombouts Yoann , Poincloux Renaud , Ben Neji Myriam , Allers Carolina , Kaushal Deepak , Kuroda Marcelo J. , Benet Susana , Martinez-Picado Javier , Izquierdo-Useros Nuria , del Carmen Sasiain Maria , Maridonneau-Parini Isabelle , Neyrolles Olivier , Vérollet Christel , Lugo-Villarino Geanncarlo
Published: November 2019

While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by whichMycobacterium tuberculosisworsens HIV-1 pathogenesis remain poorly understood. Recently, we showed that HIV-1 infection and spread are exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic analysis in these macrophages, and revealed the up-regulation of the lectin receptor Siglec-1. We demonstrate Siglec-1 expression depends on TB-mediated production of type I interferon. In co-infected non-human primates, Siglec-1 is highly expressed by alveolar macrophages, whose abundance correlates with pathology and activation of the type I interferon/STAT1 pathway. Intriguingly, Siglec-1 expression localizes exclusively on microtubule-containing TNT that are long and carry HIV-1 cargo. Siglec-1 depletion in macrophages decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer, and abrogates TB-driven exacerbation of HIV-1 infection. Altogether, we uncover a deleterious role for Siglec-1 in TB-HIV-1 co-infection, and its localization on TNT opens new avenues to understand cell-to-cell viral spread.
Thein situstructure of Parkinson’s disease-linked LRRK2
Authors: Watanabe Reika , Buschauer Robert , Böhning Jan , Audagnotto Martina , Lasker Keren , Lu Tsan Wen , Boassa Daniela , Taylor Susan , Villa Elizabeth
Published: November 2019

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Usingin situcryo-electron tomography and subtomogram averaging, we reveal a 14-Å structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double-helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase points towards the microtubule, while the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to obtain structures of previously unsolved proteins in their cellular environment and provides insights into LRRK2 function and pathogenicity.
A systematic evaluation of Mycobacterium tuberculosis Genome-Scale Metabolic Networks
Authors: López-Agudelo Víctor A , Laing Emma , Mendum Tom A , Baena Andres , Barrera Luis F , Beste Dany JV , Rios-Estepa Rigoberto
Published: November 2019

The metabolism of the causative agent of TB, Mycobacterium tuberculosis (Mtb) has recently re-emerged as an attractive drug target. A powerful approach to study Mtb metabolism is to use a systems biology framework, such as a Genome-Scale Metabolic Network (GSMN) that allows the dynamic interactions of the many individual components of metabolism to be interrogated together. Several GSMNs networks have been constructed for Mtb and used to study the complex relationship between Mtb genotype and phenotype. However, their utility is hampered by the existence of multiple models of varying properties and performances. Here we systematically evaluate eight recently published metabolic models of Mtb-H37Rv to facilitate model choice. The best performing models, sMtb2018 and iEK1011, were refined and improved for use in future studies by the TB research community.
Invasive in the North: New latitudinal record for Argentine ants in Europe
Authors: Charrier N. Pierre , Hervet Caroline , Bonsergent Claire , Charrier Matthieu , Malandrin Laurence , Kaufmann Bernard , Gippet Jérôme M. W.
Published: November 2019

Environmental niche models predict the presence of the invasive Argentine ant in north-western Europe, especially along all the French Atlantic coast. Yet, the species has never been observed North from the 45th parallel in Europe, suggesting either that current models are wrong or that Argentine ants are already spreading north inconspicuously. Here, we report a three-hectare wide colony of Argentine ants, detected in 2016 in Nantes, France, which is 300 km north of the former northern-most outdoor population of this species in Europe. COI sequencing revealed that the haplotype of this new colony is the same as the one found in the so-called Catalonian supercolony, which is distinct from the haplotype found over most of the species range in Europe. Our discovery confirms models’ predictions that Argentine ants can colonize north-western Europe and suggests that they might have already reached several other locations along the French Atlantic coast. Detection surveys should be conducted in order to assess Argentine ants’ invasion patterns in Western France, particularly in high introduction risk areas such as major cities and maritime ports.
Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington’s disease
Authors: Moreno-Delgado David , Puigdellívol Mar , Moreno Estefanía , Rodríguez-Ruiz Mar , Botta Joaquín , Gasperini Paola , Chiarlone Anna , Howell Lesley A. , Scarselli Marco , Casadó Vicent , Cortés Antoni , Ferré Sergi , Guzmán Manuel , Lluís Carme , Alberch Jordi , Canela Enric , Ginés Sílvia , McCormick Peter J.
Published: November 2019

Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD striatal cell model and HD organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD animal models at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits, as well as the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

Impact Statement

Progression of Huntington’s disease can be slowed by altering dopamine signalling through the Dopamine 1 receptor - Histamine 3 receptor heteromer.
A Hierarchical Model of the Hypothalamo-Adreno-Pituitary system
Authors: La Rota Camilo , Tudor Vuza Dan , Climescu-Haulica Adriana
Published: November 2019

We present a model of the Hypothalamo-Adreno-Pituitary (HPA) system; our approach is hierarchical and biologically sound, reflecting the complexity of the real HPA system. The structure of the conceptual model is based on theoretical frameworks of biological complex systems and its implementation takes advantage of recent hybrid automata modelling and analysis tools, being modular and reflecting parameter and mechanisms uncertainties.
PharmOmics: A Species- and Tissue-specific Drug Signature Database and Online Tool for Drug Repurposing
Authors: Chen Yen-Wei , Diamante Graciel , Ding Jessica , Nghiem Thien Xuan , Yang Jessica , Ha Sung-min , Cohn Peter , Arneson Douglas , Blencowe Montgomery , Garcia Jennifer , Zaghari Nima , Patel Paul , Yang Xia
Published: November 2019

Drug development has been hampered by a high failure rate in clinical trials due to efficacy or safety issues not predicted by preclinical studies in model systems. A key contributor is our incomplete understanding of drug functions across organ systems and species. Therefore, elucidating species- and tissue-specific actions of drugs can provide systems level insights into therapeutic efficacy, potential adverse effects, and interspecies differences that are necessary for more effective translational medicine. Here, we present a comprehensive drug knowledgebase and analytical tool, PharmOmics, comprised of genomic footprints of drugs in individual tissues from human, mouse, and rat transcriptome data from GEO, ArrayExpress, TG-GATEs, and DrugMatrix. Using multi-species and multi-tissue gene expression signatures as molecular indicators of drug functions, we developed gene network-based approaches for drug repositioning. We demonstrate the potential of PharmOmics to predict drugs for new disease indications and validated two predicted drugs for non-alcoholic fatty liver disease in mice. We also examined the potential of PharmOmics to identify drugs related to hepatoxicity and nephrotoxicity. By combining tissue- and species-specific in vivo drug signatures with biological networks, PharmOmics serves as a complementary tool to support drug characterization.
Administration of defective virus inhibits dengue transmission into mosquitoes
Authors: Mapder Tarunendu , Aaskov John , Burrage Kevin
Published: November 2019

The host-vector shuttle and the bottleneck in dengue transmission is a significant aspect with regard to the study of dengue outbreaks. As mosquitoes require 100-1000 times more virus to become infected than human, the transmission of dengue virus from human to mosquito is a vulnerability that can be targeted to improve disease control. In order to capture the heterogeneity in the infectiousness of an infected patient population towards the mosquito pool, we calibrate a population of host-to-vector virus transmission models based on an experimentally quantified infected fraction of a mosquito population. Once the population of models is well-calibrated, we deploy a population of controls that helps to inhibit the human-to-mosquito transmission of the dengue virus indirectly by reducing the viral load in the patient body fluid. We use an optimal bang-bang control on the administration of the defective virus (transmissible interfering particles, known as TIPs) to symptomatic patients in the course of their febrile period and observe the dynamics in successful reduction of dengue spread into mosquitoes.
Revisiting use of DNA characters in taxonomy with MolD - a tree independent algorithm to retrieve diagnostic nucleotide characters from monolocus datasets
Authors: Fedosov Alexander , Achaz Guillaume , Puillandre Nicolas
Published: November 2019

Abstract

While DNA characters are increasingly used for phylogenetic inference, taxa delimitation and identification, their use for formal description of taxa (i.e. providing either a formal description or a diagnosis) remains scarce and inconsistent. The impediments are neither nomenclatural, nor conceptual, but rather methodological issues: lack of agreement of what DNA character should be provided, and lack of a suitable operational algorithm to identify such characters. Furthermore, the reluctance of using DNA data in taxonomy may also be due to the concerns of insufficient reliability of DNA characters as robustness of the DNA based diagnoses has never been thoroughly assessed. Removing these impediments will enhance integrity of systematics, and will enable efficient treatment of traditionally problematic cases, such as for example, cryptic species. We have developed a novel versatile and scalable algorithmMolDto recover diagnostic combinations of nucleotides (DNCs) for pre-defined groups of DNA sequences, corresponding to taxa. We applied MolD to four published monolocus datasets to examine 1) which type of DNA characters compilation allows for more robust diagnosis, and 2) how the robustness of DNA based diagnosis changes depending on the sampled fraction of taxons diversity. We demonstrate that the redundant DNCs, termed herein sDNCs, allow for higher robustness. Furthermore, we show that a reliable DNA-based diagnosis may be obtained when a rather small fraction of the entire data set is available. Based on our results we propose improvements to the existing practices of handling DNA data in taxonomic descriptions, and discuss a workflow of contemporary systematic study, where the integrative taxonomy part precedes the proposition of a DNA based diagnosis and the diagnosis itself can be efficiently used as a DNA barcode. Our analysis fills existing methodological gaps, thus setting stage for a wider use of the DNA data in taxa description.
Cellular and synaptic adaptations of neural circuits processing skylight polarization in the fly
Authors: Sancer Gizem , Kind Emil , Uhlhorn Juliane , Volkmann Julia , Hammacher Johannes , Pham Tuyen , Plazaola-Sasieta Haritz , Wernet Mathias F.
Published: November 2019

Specialized ommatidia harboring polarization-sensitive photoreceptors exist in the ‘dorsal rim area’ (DRA) of virtually all insects. Although downstream elements have been described both anatomically and physiologically throughout the optic lobes and the central brain of different species, little is known about their cellular and synaptic adaptations and how these shape their functional role in polarization vision. We have previously shown that in the DRA of Drosophila melanogaster, two distinct types of modality-specific ‘distal medulla’ cell types (Dm-DRA1 and Dm-DRA2) are post-synaptic to long visual fiber photoreceptors R7 and R8, respectively. Here we describe additional neuronal elements in the medulla neuropil that manifest modality-specific differences in the DRA region, including DRA-specific neuronal morphology, as well as differences in the structure of pre- or post-synaptic membranes. Furthermore, we show that certain cell types (medulla tangential cells and octopaminergic neuromodulatory cells) specifically avoid contacts with polarization-sensitive photoreceptors. Finally, while certain transmedullary cells are specifically absent from DRA medulla columns, other subtypes show specific wiring differences while still connecting the DRA to the lobula complex, as previously been described in larger insects. This hints towards a complex circuit architecture with more than one pathway connecting polarization-sensitive DRA photoreceptors with the central brain.
The urinary tract microbiome in older women exhibits host genetics and environmental influences
Authors: Adebayo AS , Ackermann G , Bowyer RC , Wells P , Humphreys G , Knight R , Spector TD , Steves CJ
Published: November 2019

The urinary microbiome is a relatively unexplored niche despite the fact that we now know that it is not sterile. Moreover urinary microbes, especially in ageing populations, are associated with morbidity even when infection is subsequently not proven. We present the first large-scale study to explore factors defining urinary microbiome composition in community-dwelling older adult women without clinically active infection. Using 1600 twins, we estimate the contribution of genetic and environmental factors to variation in microbiome using both 16S and shotgun metagenomics. We found that the urinary microbiome is distinct from nearby sites and is unrelated to stool microbiome. Core urinary microbiome taxa were defined. The first component of weighted unifrac was heritable (18%) as were key taxa (e.gEscherichia-Shigella(A>0.15)). Age, menopausal status, prior UTI and host genetics were top among factors defining the urobiome. Increased composition was associated with older age, contrary to previous findings.
Elevated polygenic burden for ASD is associated with the broad autism phenotype
Authors: Nayar K. , Sealock J.M. , Maltman N. , Bush L. , Cook E.H. , Davis L.K. , Losh M.
Published: November 2019

Background

Autism spectrum disorder (ASD) is a multifactorial, neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP) have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explored polygenic scores related to the BAP.

Methods

Phenotypic and genotypic information were obtained from 2,614 trios from Simons Simplex Sample. Polygenic scores of ASD (ASD-PGS) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and Paternal ASD-PGS was explored in relation to BAP traits and their child ASD symptomatology.

Results

Maternal pragmatic language was related to child’s social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGS was related to the pragmatic language and rigid BAP domains.

Conclusions

Domain- and sex-specific associations emerged between parent and child phenotypes. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.
Pulsed electric fields create pores in the voltage sensors of voltage-gated ion channels
Authors: Rems L. , Kasimova M. A. , Testa I. , Delemotte L.
Published: November 2019

Pulsed electric fields are increasingly used in medicine to transiently increase the cell membrane permeability via electroporation, in order to deliver therapeutic molecules into the cell. One type of events that contributes to this increase in membrane permeability is the formation of pores in the membrane lipid bilayer. However, electrophysiological measurements suggest that membrane proteins are affected as well, particularly voltage-gated ion channels (VGICs). The molecular mechanisms by which the electric field could affects these molecules remain unidentified. In this study we used molecular dynamics (MD) simulations to unravel the molecular events that take place in different VGICs when exposing them to electric fields mimicking electroporation conditions. We show that electric fields induce pores in the voltage-sensor domains (VSDs) of different VGICs, and that these pores form more easily in some channels than in others. We demonstrate that poration is more likely in VSDs that are more hydrated and are electrostatically more favorable for the entry of ions. We further show that pores in VSDs can expand into so-called complex pores, which become stabilized by lipid head-groups. Our results suggest that such complex pores are considerably more stable than conventional lipid pores and their formation can lead to severe unfolding of VSDs from the channel. We anticipate that such VSDs become dysfunctional and unable to respond to changes in transmembrane voltage, which is in agreement with previous electrophyiological measurements showing a decrease in the voltage-dependent transmembrane ionic currents following pulse treatment. Finally, we discuss the possibility of activation of VGICs by submicrosecond-duration pulses. Overall our study reveals a new mechanism of electroporation through membranes containing voltage-gated ion channels.

Statement of Significance

Pulsed electric fields are often used for treatment of excitable cells, e.g., for gene delivery into skeletal muscles, ablation of the heart muscle or brain tumors. Voltage-gated ion channels (VGICs) underlie generation and propagation of action potentials in these cells, and consequently are essential for their proper function. Our study reveals the molecular mechanisms by which pulsed electric fields directly affect VGICs and addresses questions that have been previously opened by electrophysiologists. We analyze VGICs’ characteristics, which make them prone for electroporation, including hydration and electrostatic properties. This analysis is easily transferable to other membrane proteins thus opening directions for future investigations. Finally, we propose a mechanism for long-lived membrane permeability following pulse treatment, which to date remains poorly understood.
Local drug delivery to the entire cochlea without breaching its boundaries
Authors: Lukashkin Andrei N. , Sadreev Ildar I. , Zakharova Natalia , Russell Ian J. , Yarin Yury M.
Published: November 2019

The mammalian cochlea is one of the least accessible organs for drug delivery. Systemic administration of many drugs is severely limited by the blood-labyrinth barrier. Local intratympanic administration into the middle ear would be a preferable option in this case and the only option for many old and newly emerging classes of drugs but it leads to base-to-apex drug concentration gradients that are orders of magnitude and well outside the therapeutic windows. Here we present an efficient, quick, reliable and simple method of cochlear pumping, through large amplitude, low-frequency reciprocal oscillations of the stapes and round window that can consistently and uniformly deliver drugs along the entire length of the intact cochlea within minutes without disrupting cochlear boundaries. The method should facilitate novel ways of approaching the treatment of inner ear disorders since we have overcome the challenge of delivering of therapeutics along the entire length of the cochlea.

GRAPHICAL ABSTRACT
Synthetic soil crusts against green-desert transitions: a spatial model
Authors: Vidiella Blai , Sardanyés Josep , Solé Ricard V.
Published: November 2019

Semiarid ecosystems are threatened by global warming due to longer dehydration times and increasing soil degradation. Mounting evidences indicate that, given the current trends, drylands are likely to expand and possibly experience catastrophic shifts from vegetated to desert states. Here we explore a recent suggestion based on the concept of ecosystem terraformation, where a synthetic organism is used to counterbalance some of the nonlinear effects causing the presence of such tipping points. Using an explicit spatial model incorporating facilitation and considering a simplification of states found in semiarid ecosystems i.e., vegetation, fertile and desert soil, we investigate how engineered microorganisms can shape the fate of these ecosystems. Specifically, two different, but complementary, terraformation strategies are proposed:Cooperation-based:C-terraformation; andDispersion-based:D-terraformation. The first strategy involves the use of soil synthetic microorganisms to introduce cooperative loops (facilitation) with the vegetation. The second one involves the introduction of engineered microorganisms improving their dispersal capacity, thus facilitating the transition from desert to fertile soil. We show that small modifications enhancing cooperative loops can effectively change the location of the critical transition found at increasing soil degradation rates, also identifying a stronger protection against soil degradation by using theD-terraformation strategy. The same results are found in a mean field model providing insights into the transitions and dynamics tied to these terraformation strategies. The potential consequences and extensions of these models are discussed.
Same Equilibrium. Different Kinetics. Protein Functional Consequences
Authors: Schmid Sonja , Hugel Thorsten
Published: November 2019

In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein in non-specific ways.

Herein, we directly observe protein regulation in three different degrees of localization, and present the effects on the Hsp90 chaperone system at the levels of conformational equilibria, kinetics and protein function. Interestingly using single-molecule FRET, we find that similar functional and conformational steady-states are caused by completely different underlying kinetics. Solving the complete kinetic rate model allows us to disentangle specific and non-specific effects controlling Hsp90’s ATPase function, which has remained a puzzle up to this day. Lastly, we introduce a new mechanistic concept: functional stimulation through conformational confinement. Our results highlight how cellular protein regulation works by fine-tuning the conformational state space of proteins.

Significance

Proteins are perceived more and more as dynamic systems whose function depends critically on local and global flexibility. While 3D structures of proteins are frequently available today, our models often lack the time component, namely rate constants that determine protein function and regulation.

Here we used single-molecule FRET to elucidate how the chaperone protein Hsp90 is regulated on various levels, locally and globally. We find that ATPase stimulation occurs not only through specific interactions, but also non-specifically by reducing non-productive conformational flexibility; i.e. by changing kinetics rather than thermodynamics. Our work introduces ‘stimulation through conformational confinement’ as a general mechanistic concept. We anticipate that this concept plays an important role in protein regulation, phase separation, and in dynamic protein systems in general.
The accumulation of chloroplast small RNAs in unicellular algaChlamydomonas reinhardtiiis affected by nitrogen deprivation
Authors: Che-Ani Suhaimi , Azzam Ghows , Najimudin Nazalan
Published: November 2019

Small RNAs generated from the chloroplast genome may play a role in gene regulation. Given that chloroplast function is affected by nitrogen deprivation, there is yet an attempt to link chloroplast small RNAs to this stress condition. This study aims to determine the response of chloroplast small RNAs under nitrogen deprivation and their putative mode of action. A comparative transcriptomic approach was carried out to analyze the differential accumulation of chloroplast small RNAs fromChlamydomonas reinhardtiicells grown in nitrogen-deprived versus nitrogen-based medium. A total of 101 chloroplast small RNA candidates were successfully annotated. Growth in nitrogen-deprived medium revealed 17 significantly upregulated and 12 downregulated chloroplast small RNAs. These chloroplast small RNAs originated from different genomic locations such as untranslated, intergenic or antisense regions as well as the ends of tRNA and rRNA genes. The differentially accumulated csRNAs from 3’-untranslated regions were all upregulated. In contrast, the csRNAs from the ends of tRNA and rRNA genes were all downregulated during nitrogen deprivation. Fluctuations of the chloroplast small RNA levels indicated their importance in the chloroplasts during changes in nitrogen levels. The primary sequences of three selected chloroplast small RNA were found to be conserved in the chloroplast genomes of a few microalgae, again reflecting their functional importance. The findings from this study provided new insights into the involvement of non-coding RNAs in chloroplast during metabolic stress.
Unpaired Data Empowers Association Tests
Authors: Gong Mingming , Liu Peng , Sciurba Frank C. , Stojanov Petar , Tao Dacheng , Tseng George C. , Zhang Kun , Batmanghelich Kayhan
Published: November 2019

To achieve a holistic view of the underlying mechanisms of human diseases, the biomedical research community is moving toward harvesting retrospective data available in Electronic Healthcare Records (EHRs). The first step for causal understanding is to perform association tests between types of potentially high-dimensional biomedical data, such as genetic, blood biomarkers, and imaging data. To obtain a reasonable power, current methods require a substantial sample size of individuals with both data modalities. This prevents researchers from using much larger EHR samples that include individuals with at least one data type, limits the power of the association test, and may result in higher false discovery rate. We present a new method called the Semi-paired Association Test (SAT) that makes use of both paired and unpaired data. In contrast to classical approaches, incorporating unpaired data allows SAT to produce better control of false discovery and, under some conditions, improve the association test power. We study the properties of SAT theoretically and empirically, through simulations and application to real studies in the context of Chronic Obstructive Pulmonary Disease. Our method identifies an association between the high-dimensional characterization of Computed Tomography (CT) chest images and blood biomarkers as well as the expression of dozens of genes involved in the immune system.
An rpw8 quadruple mutant of Arabidopsis Col-0 is partially compromised in bacterial and fungal resistance
Authors: Castel Baptiste , Wu Yan , Xiao Shunyuan , Jones Jonathan D G
Published: November 2019

The plant immune system relies on both cell-surface and intracellular NLR (nucleotide-binding, leucine-rich repeat) receptors. NLRs respond to pathogen effectors and activate effector-triggered immunity: a cocktail of responses, often accompanied by cell death, resulting in resistance.

RPW8 encodes an unusual non-NLR Resistance (R) protein and confers broad-spectrum powdery mildew resistance. It requires genetic components also required by some NLRs, resembles the HeLo-containing protein MLKL (necroptosis executor in animals) and HET-S (cell death executor in fungi) and is targeted to the extra-haustorial membrane during powdery mildew infection by its N-terminal non-cleaved signal anchor domain. RPW8 displays extensive recent duplication events in Arabidopsis and certain alleles can induce oligomerisation-dependent activation of the NLR RPP7.

All these features enabled us to formulate hypotheses for RPW8 function: (1) RPW8 could be a cell death executor for defence against pathogens. (2) RPW8 could be a decoy for effector targets.

To test these hypotheses, we generated a quadruple knock-out mutant of the four RPW8-homologous copies in Arabidopsis Col-0, using CRISPR. The mutant still displays cell death upon activation of four well-characterised NLRs. However, it is partially impaired in powdery mildew resistance and also in bacterial resistance. Interestingly Col-0_rpw8 is delayed in flowering transition. In conclusion, RPW8 plays a broad role in immunity and plant development, beyond resistance to powdery mildew. There is no evidence that it is involved in executing ETI-associated cell death.
Bis(4-hydroxy-N,N-di-n-propyltryptammonium) fumarate tetrahydrate
Authors: Chadeayne Andrew R. , Pham Duyen N. K. , Golen James A. , Manke David R.
Published: November 2019

The title compound (systematic name: bis{[2-(4-hydroxy-1H-indol-3-yl)ethyl]bis(propan-2-yl)azanium} but-2-enedioate tetrahydrate), 2C16H25N2O+·C4H2O4
2−·4H2O, has a singly protonated DPT cation, one half of a fumarate dianion (completed by a crystallographic centre of symmetry) and two water molecules of crystallization in the asymmetric unit. A series of N—H...O and O—H...O hydrogen bonds form a three-dimensional network in the solid state.
CEO age and analysts forecast properties
Authors: Haider Imran , Sultana Nigar , Singh Harjinder , Tham Yeut Hong
Published: November 2019

Purpose

The purpose of this paper is to assess whether there is an association between CEO age and analysts forecast properties (particularly forecast accuracy and bias/optimism). CEOs, having the central role in managing firms, can significantly influence the financial and non-financial decisions in an organisation. Furthermore, having been identified as key culprits in past major accounting scandals, it is also important to identify the CEO characteristics that affect financial reporting decisions.

Design/methodology/approach

This study adopts the upper echelon theory on the relationship between CEO age and analysts forecast properties. The authors use a sample of 2,730 Australian firm-year observations for the period 2004–2013 drawn from IBES, Connect 4 and SIRCA databases.

Findings

The authors find that analyst forecast accuracy increases and bias (optimism) reduces with the CEO age. The authors conclude that earnings and related information provided to analysts improves with the CEO age, which increases the forecast accuracy and reduces bias (optimism). Additional results suggest that the positive (negative) effect of CEO age on forecast accuracy (bias) remains until the CEOs reach the age of their retirement age (65 years). The results remain consistent with a number of sensitivity tests and provide implication for stakeholders such as firms, analysts, auditors, financial statements users and regulators.

Practical implications

The authors demonstrate that the relationship between CEO age and analyst forecast properties is not linear but is, in fact, curvilinear substantiating concerns that CEOs that are much younger or much older do not help increase the quality of the information environment. Consequently, firms hiring CEOs in the right age bracket also benefit by having higher-quality information environment leading possibly to reduce costs such as those relating to debt and/or equity ultimately increasing firm value.

Originality/value

Empirical studies on the association between CEO age and analysts earnings properties in Australia are scarce and this paper contributes to the determinants of the analysts forecast accuracy and bias (optimism) and the CEO age literature.
Explaining university student loyalty: theory, method, and empirical research in Chile
Authors: Gallegos Juan Alejandro , Vasquez Arturo
Published: November 2019

Purpose

The purpose of this paper is to explain student loyalty beyond its customary relationship with student satisfaction by including two relational variables, trust and commitment, two cognitive traits (service familiarity and communication) and one affective trait (opportunism) as moderators of the impact of trust and commitment on loyalty.

Design/methodology/approach

Two relational constructs (trust and commitment) are employed to improve the loyalty model and key comparisons are performed to know if career, cohort and sourcing school generate differences in the explanation of student loyalty.

Findings

Results show that the explanation chain that starts with student satisfaction but continues with the development of student trust and the reaching of student commitment culminates with student loyalty. The moderators (student opportunism, service familiarity, communication, age and available income for education) significantly contribute to the explanatory power of the model. Career is a meaningful differentiator in reaching student loyalty as are student cohort and the type of high school from which the student came.

Research limitations/implications

This is one of first empirical studies on university student loyalty. Future research could test the same or new hypotheses using different samples and contexts.

Practical implications

University policies may benefit from the inclusion of norms regarding relational processes and outcomes such as the value of trust in the interactions and systematic recognition and awards assigned to student commitment achievements.

Originality/value

The explanation chain of customer loyalty was successfully applied to student loyalty, and strengthened with the addition of meaningful moderating variables.
Web scraping for food price research
Authors: Hillen Judith
Published: November 2019

Purpose

The purpose of this paper is to discuss web scraping as a method for extracting large amounts of data from online sources. The author wants to raise awareness of the method’s potential in the field of food price research, hoping to enable fellow researchers to apply this method.

Design/methodology/approach

The author explains the technical procedure of web scraping, reviews the existing literature, and identifies areas of application and limitations for food price research.

Findings

The author finds that web scraping is a promising method to collect customised, high-frequency data in real time, overcoming several limitations of currently used food price data sources. With today’s applications mostly focussing on (online) consumer prices, the scope of applications for web scraping broadens as more and more price data are published online.

Research limitations/implications

To better deal with the technical and legal challenges of web scraping and to exploit its scalability, joint data collection projects in the field of agricultural and food economics should be considered.

Originality/value

In agricultural and food economics, web scraping as a data collection technique has received little attention. This is one of the first articles to address this topic with particular focus on food price analysis.
The effects of relationship bonds on bank employees’ psychological responses and boundary-spanning behaviors
Authors: Lee Myoung-Soung , Han Sang-Lin
Published: November 2019

Purpose

The purpose of this paper is to examine the effects of relationship bonds on the psychological response and behavior of bank employees based on the job demands–resources theory. Specifically, it examines the effects of relationship bonds in terms of person–job (P–J) fit, emotional exhaustion, job satisfaction and boundary-spanning behaviors, all of which comprise the behavioral dimensions of bank employees. In addition, the study examines how the resiliency of bank employees influences their emotional exhaustion and determines whether a moderating effect related to emotional exhaustion exists.

Design/methodology/approach

To achieve this aim, data were collected from 365 customer-facing banking employees in South Korea. Reliability, validity and the hypotheses were verified through structural equation modeling; any moderating effects were identified using the bootstrap method and the process model.

Findings

Study results showed that financial, structural, internal social and external social bonds – the bonds pertaining to relationship elements – have positive effects on P–J fit. P–J fit influenced emotional exhaustion negatively and job satisfaction positively. Furthermore, emotional exhaustion negatively influenced job satisfaction. Job satisfaction had positive effects on service delivery, external representation and internal influence, the elements comprising boundary-spanning behavior. Finally, resiliency was shown to lower emotional exhaustion but revealed no moderating effect.

Originality/value

First, this study examined relationship bonds, which reference relationship marketing when introducing organizational resources that influence the psychological and behavioral responses of bank employees. Second, this study introduced resiliency as a personal resource and clarified the way it applies to an individual’s psychological response. Third, existing literature has been limited to conducting fragmented research of the psychological factors that intervene in predisposing factors and job outcomes. This study makes a unique contribution by establishing a psychological response process.