bluuebunny/crossref_metadata_2025 huggingface dataset:
IsomericO-methyl cannabidiolquinones with dual BACH1/NRF2 activity
Authors: Casares Laura , Unciti Juan Diego , Prados Maria Eugenia , Caprioglio Diego , Higgins Maureen , Apendino Giovanni , Dinkova-Kostova Albena T. , Muñoz Eduardo , de la Vega Laureano
Published: June 2020

Oxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington’s disease, setting the basis for further developmentsin vivo.
PEDIGREE ANALYSIS OF 222 ALMOND GENOTYPES REVEALS TWO WORLD MAINSTREAM BREEDING LINES BASED ON ONLY THREE DIFFERENT CULTIVARS
Authors: de los Cobos Felipe Pérez , Martínez-García Pedro J. , Romero Agustí , Miarnau Xavier , Eduardo Iban , Howad Werner , Dicenta Federico ,   Rafel Socias i Company, Rubio Maria J. , Gradziel Thomas M. , Whirthensohn Michelle , Duval Henri , Holland Doron , Arús Pere , Vargas Francisco J. , Batlle Ignasi
Published: June 2020

Loss of genetic variability is a steadily increasing challenge in tree breeding programs due to the repeated use of a reduced number of founder genotypes. High-quality pedigree data of 222 almond [Prunus dulcis(Miller) D.A. Webb, syn.P. amygdalus(L) Batsch] cultivars and breeding selections were used to study global genetic variability in modern breeding programs from Argentina, Australia, France, Greece, Israel, Italy, Russia, Spain and the USA. Inbreeding coefficients, pairwise relatedness and genetic contribution were calculated for these genotypes. The results reveal two mainstream breeding lines based on three cultivars from two different geographical regions: ‘Tuono’-‘Cristomorto’ (local landraces from Puglia, Italy) and ‘Nonpareil’ (chance seedling selected in California, USA, from French original stock). Direct descendants from ‘Tuono’ or ‘Cristomorto’ number 75 (sharing 30 descendants), while ‘Nonpareil’ has 72 direct descendants. The mean inbreeding coefficient of the analyzed genotypes was 0.036, with 13 genotypes presenting a high inbreeding coefficient, over 0.250. Breeding programs from the USA, France and Spain showed inbreeding coefficients of 0.067, 0.050 and 0.034, respectively. According to their genetic contribution, modern cultivars from Israel, France, the USA, Spain and Australia, trace back to six, five, four, four and two main founding genotypes respectively. Among the group of 65 genotypes carrying theSfallele for self-compatibility, the mean relatedness coefficient was 0.133, with ‘Tuono’ as the main founding genotype (23.75% of total genetic contribution). Increasing as well as preserving current genetic variability is required in almond breeding programs worldwide to assure genetic gain and continuing breeding progress. Breeding objectives, apart from high and efficient productivity, should include disease resistance and adaptation to climate change. Ultimately, any new commercial almond cultivar has to be economically viable and breeders play a critical role in achieving this goal.
Continuum dynamics and statistical correction of compositional heterogeneity in multivalent IDP oligomers resolved by single-particle EM
Authors: Mostofian Barmak , McFarland Russell , Estelle Aidan , Howe Jesse , Barbar Elisar , Reichow Steve L. , Zuckerman Daniel M.
Published: June 2020

Multivalent intrinsically disordered protein (IDP) complexes are prevalent in biology and control diverse cellular functions, including tuning levels of transcription, coordinating cell-signaling events, and regulating the assembly and disassembly of complex macromolecular architectures. These systems pose a significant challenge to structural investigation, due to the continuum dynamics imparted by the IDP and compositional heterogeneity resulting from characteristic low-affinity interactions. Traditional single-particle electron microscopy (EM) is a powerful tool for visualizing IDP complexes. However, the IDPs themselves are typically “invisible” by EM, undermining methods of image analysis and structural interpretation. To overcome these challenges, we developed a pipeline for automated analysis of common ‘beads-on-a-string’ type of assemblies, composed of IDPs bound at multivalent sites to the ubiquitous ~20 kDa cross-linking hub protein LC8. This approach quantifies conformational and compositional heterogeneity on a single-particle basis, and statistically corrects spurious observations arising from random proximity of bound and unbound LC8. After careful validation of the methodology, the approach was applied to the nuclear pore IDP Nup159 and the transcription factor ASCIZ. The analysis unveiled significant compositional and conformational diversity in both systems that could not be obtained from traditional single particle EM class-averaging strategies, and shed new light on how these architectural properties contribute to their physiological roles in supramolecular assembly and transcriptional regulation. Ultimately, we expect that this approach may be adopted to many other intrinsically disordered systems that have evaded traditional methods of structural characterization.

Significance Statement

Intrinsically disordered proteins (IDPs) or protein regions (IDRs) represent >30% of the human proteome, but mechanistically remain some of the most poorly understood classes of proteins in biology. This dearth in understanding stems from these very same intrinsic and dynamic properties, which make them difficult targets for quantitative and structural characterization. Here, we present an automated approach for extracting quantitative descriptions of conformational and compositional heterogeneity present in a common ‘beads-on-a-string’ type of multivalent IDP system from single-particle images in electron micrographs. This promising approach may be adopted to many other intrinsically disordered systems that have evaded traditional ensemble methods of characterization.
ppGpp is a bacterial cell size regulator
Authors: Büke Ferhat , Grilli Jacopo , Lagomarsino Marco Cosentino , Bokinsky Gregory , Tans Sander
Published: June 2020

Growth and division are central to cell size. Bacteria achieve size homeostasis by dividing when growth has added a constant size since birth, termed the “adder” principle, by unknown mechanisms [1–4]. Growth is well known to be regulated by ppGpp, which controls anything from ribosome production to metabolic enzyme activity and replication initiation, and whose absence or excess can induce the stress response, filamentation, and yield growth-arrested miniature cells [5–8]. These observations raise unresolved questions about the relation between ppGpp and size homeostasis mechanisms during normal exponential growth. Here, to untangle effects of ppGpp and nutrients, we gained control of cellular ppGpp by inducing the synthesis and hydrolysis enzymes RelA and Mesh1. We found that ppGpp not only exerts control over the growth rate, but also over cell division and hence the steady state cell size. The added size responds rapidly to changes in the ppGpp level, aided by transiently accelerated or delayed divisions, and establishes its new constant value while the growth rate still adjusts. Moreover, the magnitude of the added size and resulting steady-state birth size correlate consistently with the ppGpp level, rather than with the growth rate, which results in cells of different size that grow equally fast. Our findings suggest that ppGpp serves as a critical regulator that coordinates cell size and growth control.
System Identification with Biophysical Constraints: A Circuit Model of the Inner Retina
Authors: Schröder Cornelius , Klindt David , Strauss Sarah , Franke Katrin , Bethge Matthias , Euler Thomas , Berens Philipp
Published: June 2020

Visual processing in the retina has been studied in great detail at all levels such that a comprehensive picture of the retina’s cell types and the many neural circuits they form is emerging. However, the currently best performing models of retinal func­tion are black-box CNN models which are agnostic to such biological knowledge. In particular, these models typically neglect the role of the many inhibitory circuits involving amacrine cells and the biophysical mechanisms underlying synaptic release. Here, we present a computational model of temporal processing in the inner retina, including inhibitory feedback circuits and realistic synaptic release mechanisms. Fit to the responses of bipolar cells, the model generalized well to new stimuli including natural movie sequences, performing on par with or better than a benchmark black-box model. In pharmacology experiments, the model replicatedin silicothe effect of blocking specific amacrine cell populations with high fidelity, indicating that it had learned key circuit functions. Also, more in depth comparisons showed that connectivity patterns learned by the model were well matched to connectivity patterns extracted from connectomics data. Thus, our model provides a biologically interpretable data-driven account of temporal processing in the inner retina, filling the gap between purely black-box and detailed biophysical modeling.
Breast Cancer Cells and Macrophages in a Paracrine-Juxtacrine Loop
Authors: Onal Sevgi , Turker-Burhan Merve , Bati-Ayaz Gizem , Yanik Hamdullah , Pesen-Okvur Devrim
Published: June 2020

Breast cancer cells (BCC) and macrophages are known to interact via epidermal growth factor (EGF) produced by macrophages and colony stimulating factor-1 (CSF-1) produced by BCC. Despite contradictory findings, this interaction is perceived as a paracrine loop. Further, the underlying mechanism of interaction remains unclear. Here, we investigated interactions of BCC with macrophages in 2D and 3D. BCC did not show chemotaxis to macrophages in custom designed 3D cell-on-a-chip devices, which was in agreement with ELISA results showing that macrophage-derived-EGF was not secreted into macrophage-conditioned-medium. Live cell imaging of BCC in the presence and absence of iressa showed that macrophages but not macrophage-derived-matrix modulated adhesion and motility of BCC in 2D. 3D co-culture experiments in collagen and matrigel showed that BCC changed their multicellular organization in the presence of macrophages. In custom designed 3D co-culture cell-on-a-chip devices, macrophages promoted and reduced migration of BCC in collagen and matrigel, respectively. Furthermore, adherent but not suspended BCC endocytosed EGFR when in contact with macrophages. Collectively, our data revealed that macrophages showed chemotaxis towards BCC whereas BCC required direct contact to interact with macrophage-derived-EGF. We propose that the interaction between cancer cells and macrophages is a paracrine-juxtacrine loop of CSF-1 and EGF, respectively.
Remodeling mechanisms determine size distributions in developing retinal vasculature
Authors: Iizuka Osamu , Kawamura Shotaro , Tero Atsushi , Uemura Akiyoshi , Miura Takashi
Published: June 2020

The development of retinal blood vessels has extensively been used as a model to study vascular pattern formation. To date, various quantitative measurements, such as size distribution have been performed, but the relationship between pattern formation mechanisms and these measurements remains unclear. In the present study, we first quantitatively measured the island size distribution in the retinal vascular network and found that it tended to exhibit an exponential distribution. We were able to recapitulate this distribution pattern in a theoretical model by implementing the stochastic disappearance of vessel segments around arteries could reproduce the observed exponential distribution of islands. Second, we observed that the diameter distribution of the retinal artery segment obeyed a power law;. We theoretically showed that an equal bifurcation branch pattern and Murray’s law could reproduce this pattern. This study demonstrates the utility of examining size distribution for understanding the mechanisms of vascular pattern formation.
Microfluidic characterization of macromolecular liquid-liquid phase separation
Authors: Bremer Anne , Mittag Tanja , Heymann Michael
Published: June 2020

Liquid-liquid phase separation plays important roles in the compartmentalization of cells. Developing an understanding of how phase separation is encoded in biomacromolecules requires quantitative mapping of their phase behavior. Given that such experiments require large quantities of the biomolecule of interest, these efforts have been lagging behind the recent breadth of biological insights. Herein, we present a microfluidic phase chip that enables the measurement of saturation concentrations over at least three orders of magnitude for a broad spectrum of biomolecules and solution conditions. The phase chip consists of five units, each made of twenty individual sample chambers to allow the measurement of five sample conditions simultaneously. The analytes are slowly concentrated via evaporation of water, which is replaced by oil, until the sample undergoes phase separation into a dilute and dense phase. We show that the phase chip lowers the required sample quantity by 98% while offering six-fold better statistics in comparison to standard manual experiments that involve centrifugal separation of dilute and dense phase. We further show that the saturation concentrations measured in chip are in agreement with previously reported data for a variety of biomolecules. Concomitantly, time-dependent changes of the dense phase morphology and potential off-pathway processes, including aggregation, can be monitored microscopically. In summary, the phase chip is suited to exploring sequence-to-binodal relationships by enabling the determination of a large number of saturation concentrations at low protein cost.
Lack of susceptibility of poultry to SARS-CoV-2 and MERS-CoV
Authors: Suarez David L. , Pantin-Jackwood Mary J. , Swayne David E. , Lee Scott A. , DeBlois Suzanne M. , Spackman Erica
Published: June 2020

Chickens, turkeys, ducks, quail and geese were challenged with SARS-CoV-2 or MERS-CoV. No disease was observed, no virus replication was detected, and antibodies were not detected in serum. Neither virus replicated in embryonating chicken’s eggs. Poultry are unlikely to serve a role in the maintenance of either virus.
MOCCASIN: A method for correcting for known and unknown confounders in RNA splicing analysis
Authors: Slaff Barry , Radens Caleb M , Jewell Paul , Jha Anupama , Lahens Nicholas F , Grant Gregory R , Thomas-Tikhonenko Andrei , Lynch Kristen W. , Barash Yoseph
Published: June 2020

While the effects of confounders on gene expression analysis have been extensively studied there is a lack of equivalent analysis and tools for RNA splicing analysis. Here we assess the effect of confounders in two large public RNA-Seq datasets (TARGET, ENCODE), develop a new method, MOCCASIN, to correct the effect of both known and unknown confounders on RNA splicing quantification, and demonstrate MOCCASIN’s effectiveness on both synthetic and real data.
Helical ensembles out-perform ideal helices in Molecular Replacement
Authors: Rodríguez Filomeno Sánchez , Simpkin Adam J. , Davies Owen R. , Keegan Ronan M. , Rigden Daniel J.
Published: June 2020

The conventional approach in molecular replacement (MR) is the use of a related structure as a search model. However, this is not always possible as the availability of such structures can be scarce for poorly characterised families of proteins. In these cases, alternative approaches can be explored, such as the use of small ideal fragments that share high albeit local structural similarity with the unknown protein. Earlier versions ofAMPLEenabled the trialling of a library of ideal helices, which worked well for largely helical proteins at suitable resolution. Here we explore the performance of libraries of helical ensembles created by clustering helical segments. The impacts of different B-factor treatments and different degrees of structural heterogeneity are explored. We observed a 30% increase in the number of solutions obtained byAMPLEwhen using this new set of ensembles compared to performance with ideal helices. The boost of performance was notable across three different folds: transmembrane, globular and coiled-coil structures. Furthermore, the increased effectiveness of these ensembles was coupled to a reduction of the time required byAMPLEto reach a solution.AMPLEusers can now take full advantage of this new library of search models by activating the “helical ensembles” mode.
Structural basis for tuning activity and membrane specificity of bacterial cytolysins
Authors: Shah Nita R. , Voisin Tomas B. , Parsons Edward S. , Boyd Courtney M. , Hoogenboom Bart W. , Bubeck Doryen
Published: June 2020

Cholesterol-dependent cytolysins (CDCs) form protein nanopores to lyse cells. They target eukaryotic cells using different mechanisms, but all require the presence of cholesterol to pierce lipid bilayers. How CDCs use cholesterol to selectively lyse cells is essential for understanding virulence strategies of several pathogenic bacteria, and for repurposing CDCs to kill new cellular targets. Here we address that question by trapping an early state of pore formation for the CDC intermedilysin, bound to the human immune receptor CD59 in a nanodisc model membrane. Our cryo-electron microscopy map reveals structural transitions required for oligomerization, which include the lateral movement of a key amphipathic helix. We demonstrate that the charge of this helix is crucial for tuning lytic activity of CDCs. Furthermore, we discover modifications that overcome the requirement of cholesterol for membrane rupture, which will facilitate engineering the target-cell specificity of pore-forming proteins.
Advanced age attenuates the antihyperalgesic effect of morphine and decreases μ-opioid receptor expression and binding in the rat midbrain Periaqueductal Gray in male and female rats
Authors: Fullerton Evan F. , Rubaharan Myurajan , Karom Mary C. , Hanberry Richard I. , Murphy Anne Z.
Published: June 2020

The present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral PAG (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of Complete Freund’s adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3mos) and aged (16-18mos) male and female rats. Morphine potency was highest in adult males, with a two-fold decrease in morphine EC50observed in aged versus adult males (10.22mg/kg versus 5.19mg/kg). Adult and aged female rats also exhibited significantly higher EC50values (10.69 mg/kg and 9.00 mg/kg, respectively) compared to adult males. The upward shift in EC50from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.
Asbestos accelerates disease onset in a genetic model of Malignant Pleural Mesothelioma
Authors: Farahmand Pooyeh , Gyuraszova Katarina , Rooney Claire , Raffo-Iraolagoitia Ximena L. , Johnson Emma , Chernova Tatiana , Monteverde Tiziana , Blyth Kevin , Duffin Roger , Carlin Leo M. , Lewis David , le Quesne John , MacFarlane Marion , Murphy Daniel J.
Published: June 2020

Hypothesis

Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations.

Methods

Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration.

Results

Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours initiated in the presence of asbestos showed increased macrophage infiltration. Single-agent suppression of macrophages in mice with established tumours failed to extend survival.

Conclusion

Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages alone in established disease showed no therapeutic benefit.
Influence of the lab adopted natural diet and environmental and parental microbiota on life history and metabolic phenotype ofDrosophila melanogasterlarvae
Authors: Bombin Andrei , Cunneely Owen , Eickman Kira , Bombin Sergei , Ruesy Abigail , Abigail Myers Mengting Su , Cowan Rachael , Reed Laura
Published: June 2020

Obesity is an increasing worldwide epidemic and contributes to physical and mental health losses. The development of obesity is caused by multiple factors including genotype, hormonal misregulation, psychological stress, and gut microbiota. Our project investigated the effects produced by microbiota community, acquired from the environment and horizontal transfer, on traits related to obesity. The study applied a novel approach of raisingDrosophila melanogasterfrom ten, wild-derived genetic lines (DGRP) on naturally fermented peaches, thereby preserving genuine microbial conditions. Our results indicated that larvae raised on the natural and standard lab diets were significantly different from each other in every tested phenotype. In addition, sterilized larvae raised on the autoclaved peach diet, therefore exposed to natural nutritional stress but lacking natural microbiota community, were associated with adverse phenotypes such as low survival rate, longer developmental time, smaller weight, and elevated triglyceride and glucose levels. Our findings suggested that frozen peach food provided nutritional conditions similar to the natural ones and preserved key microbial taxa necessary for survival and development ofDrosophilalarvae. The presence of parental microbiota did not produce a significant effect on any of the tested phenotypes when larvae were raised on the lab diet. Contrarily, on the peach diet, the presence of parental microbiota increased the weight and development rate, even if the original peach microbiota were still present. In addition, we found that larvae raised on the peach diet formed a microbial community distinctive from larvae raised on the lab or peach autoclaved diets. The effect that individual microbial taxa produced on the host varied significantly with changing environmental and genetic conditions, occasionally to the degree of opposite correlations.
Agreement and uncertainty among climate change impact models: A synthesis of sagebrush steppe vegetation projections
Authors: Zimmer Scott N. , Grosklos Guenchik J. , Belmont Patrick , Adler Peter B.
Published: June 2020

Ecologists have built numerous models to project how climate change will impact rangeland vegetation, but these projections are difficult to validate, making their utility for land management planning unclear. In the absence of direct validation, researchers can ask whether projections from different models are consistent. High consistency across models based on different assumptions and emission scenarios would increase confidence in using projections for planning. Here, we analyzed 42 models of climate change impacts on sagebrush (Artemisia tridentataNutt.), cheatgrass (Bromus tectorumL.), pinyon-juniper (PinusL.spp. andJuniperusL.spp.), and forage production on Bureau of Land Management (BLM) lands in the United States Intermountain West. These models consistently projected the potential for pinyon-juniper declines and forage production increases. In contrast, cheatgrass models mainly projected no climate change impacts, while sagebrush models projected no change in most areas and declines in southern extremes. In most instances, vegetation projections from high and low emissions scenarios differed only slightly.

The projected vegetation impacts have important management implications for agencies such as the BLM. Pinyon-juniper declines would reduce the need to control pinyon-juniper encroachment, and increases in forage production could benefit livestock and wildlife populations in some regions. Sagebrush conservation and restoration projects may be challenged in areas projected to experience sagebrush declines. However, projected vegetation impacts may also interact with increasing future wildfire risk in ways single-response models do not anticipate. In particular, forage production increases could increase management challenges related to fire.
3D bioprinting of co-cultured osteogenic spheroids for bone tissue fabrication
Authors: Heo Dong Nyoung , Ayan Bugra , Dey Madhuri , Banerjee Dishary , Wee Hwabok , Lewis Gregory S. , Ozbolat Ibrahim T.
Published: June 2020

Conventional top-down approaches in tissue engineering involving cell seeding on scaffolds have been widely used in bone engineering applications. However, scaffold-based bone tissue constructs have had limited clinical translation due to constrains in supporting scaffolds, minimal flexibility in tuning scaffold degradation, and low achievable cell seeding density as compared with native bone tissue. Here, we demonstrate a pragmatic and scalable bottom-up method, inspired from embryonic developmental biology, to build three-dimensional (3D) scaffold-free constructs using spheroids as building blocks. Human umbilical vein endothelial cells (HUVECs) were introduced to human mesenchymal stem cells (hMSCs) (hMSC/HUVEC) and spheroids were fabricated by an aggregate culture system. Bone tissue was generated by induction of osteogenic differentiation in hMSC/HUVEC spheroids for 10 days, with enhanced osteogenic differentiation and cell viability in the core of the spheroids compared to hMSC-only spheroids. Aspiration-assisted bioprinting (AAB) is a new bioprinting technique which allows precise positioning of spheroids (11% with respect to the spheroid diameter) by employing aspiration to lift individual spheroids and bioprint them onto a hydrogel. AAB facilitated bioprinting of scaffold-free bone tissue constructs using the pre-differentiated hMSC/HUVEC spheroids. These constructs demonstrated negligible changes in their shape for two days after bioprinting owing to the reduced proliferative potential of differentiated stem cells. Bioprinted bone tissues showed interconnectivity with actin-filament formation and high expression of osteogenic and endothelial-specific gene factors. This study thus presents a viable approach for 3D bioprinting of complex-shaped geometries using spheroids as building blocks, which can be used for various applications including but not limited to, tissue engineering, organ-on-a-chip and microfluidic devices, drug screening and, disease modeling.
Transcriptogram analysis reveals relationship between viral titer and gene sets responses during Corona-virus infection
Authors: de Almeida Rita M.C. , Thomas Gilberto L. , Glazier James A.
Published: June 2020

To understand the difference between benign and severe outcomes after Coronavirus infection, we urgently need ways to clarify and quantify the time course of tissue and immune responses. Here we re-analyze 72-hour time-series microarrays generated in 2013 by Sims and collaborators for SARS-CoV-1in vitroinfection of a human lung epithelial cell line. Transcriptograms, a Bioinformatics tool to analyze genome-wide gene expression data, allow us to define an appropriate context-dependent threshold for mechanistic relevance of gene differential expression. Without knowing in advance which genes are relevant, classical analyses detecteverygene with statistically-significant differential expression, leaving us with too many genes and hypotheses to be useful. Using a Transcriptogram-based top-down approach, we identified three major, differentially-expressed gene sets comprising 219 mainly immune-response-related genes. We identified timescales for alterations in mitochondrial activity, signaling and transcription regulation of the innate and adaptive immune systems and their relationship to viral titer. At the individual-gene level, EGR3 was significantly upregulated in infected cells. Similar activation in T-cells and fibroblasts in infected lung could explain the T-cell anergy and eventual fibrosis seen in SARS-CoV-1 infection. The methods can be applied to RNA data sets for SARS-CoV-2 to investigate the origin of differential responses in different tissue types, or due to immune or preexisting conditions or to compare cell culture, organoid culture, animal models, and human-derived samples.
Uncovering temporally sensitive targeting motifs for traumatic brain injury via phage display
Authors: Martinez Briana I. , Mousa Gergey Alzaem , Fleck Kiera , MacCulloch Tara , Diehnelt Chris W. , Stephanopoulos Nicholas , Stabenfeldt Sarah E.
Published: June 2020

The heterogeneous injury pathophysiology of traumatic brain injury (TBI) is a barrier to developing highly sensitive and specific diagnostic tools. Embracing neural injury complexity is critical for the development and advancement of diagnostics and therapeutics. The current study employs a unique discovery pipeline to identify targeting motifs that recognize specific phases of TBI pathology. This pipeline entailsin vivobiopanning with a domain antibody (dAb) phage display library, next generation sequencing (NGS) analysis, and peptide synthesis. Here, we identify targeting motifs based on the HCDR3 structure of dAbs for acute (1 day) and subacute (7 days) post-injury timepoints using a mouse controlled cortical impact model. Their bioreactivity was validated using immunohistochemistry and candidate target epitopes were identified via immunoprecipitation-mass spectrometry. The acute targeting motif recognizes targets associated with metabolic and mitochondrial dysfunction whereas the subacute motif was largely associated with neurodegenerative processes. This phage display biomarker discovery pipeline for TBI successfully achieved discovery of temporally specific TBI targeting motif/epitope pairs that will advance the TBI diagnostics and therapeutics.
Dissociation of task engagement and arousal effects in auditory cortex and midbrain
Authors: Saderi Daniela , Schwartz Zachary P. , Heller Charlie R. , Pennington Jacob R. , David Stephen V.
Published: June 2020

Both generalized arousal and engagement in a specific task influence sensory neural processing. To isolate effects of these state variables in the auditory system, we recorded single-unit activity from primary auditory cortex (A1) and inferior colliculus (IC) of ferrets during a tone detection task, while monitoring arousal via changes in pupil size. We used a generalized linear model to assess the influence of task engagement and pupil size on sound-evoked activity. In both areas, these two variables affected independent neural populations. Pupil size effects were more prominent in IC, while pupil and task engagement effects were equally likely in A1. Task engagement was correlated with larger pupil; thus, some apparent effects of task engagement should in fact be attributed to fluctuations in pupil size. These results indicate a hierarchy of auditory processing, where generalized arousal enhances activity in midbrain, and effects specific to task engagement become more prominent in cortex.
Identification of key tissue-specific, biological processes by integrating enhancer information in maize gene regulatory networks
Authors: Fagny Maud , Kuijjer Marieke Lydia , Stam Maike , Joets Johann , Turc Olivier , Rozière Julien , Pateyron Stéphanie , Venon Anthony , Vitte Clémentine
Published: June 2020

Enhancers are important regulators of gene expression during numerous crucial processes including tissue differentiation across development. In plants, their recent molecular characterization revealed their capacity to activate the expression of several target genes through the binding of transcription factors. Nevertheless, identifying these target genes at a genome-wide level remains a challenge, in particular in species with large genomes, where enhancers and target genes can be hundreds of kilobases away. Therefore, the contribution of enhancers to regulatory network is still poorly understood in plants. In this study, we investigate the enhancer-driven regulatory network of two maize tissues at different stages: leaves at seedling stage and husks (bracts) at flowering. Using a systems biology approach, we integrate genomic, epigenomic and transcriptomic data to model the regulatory relationship between transcription factors and their potential target genes. We identify regulatory modules specific to husk and V2-IST, and show that they are involved in distinct functions related to the biology of each tissue. We evidence enhancers exhibiting binding sites for two distinct transcription factor families (DOF and AP2/ERF) that drive the tissue-specificity of gene expression in seedling immature leaf and husk. Analysis of the corresponding enhancer sequences reveals that two different transposable element families (TIR transposonMutatorand MITEPif/Harbinger) have shaped the regulatory network in each tissue, and that MITEs have provided new transcription factor binding sites that are involved in husk tissue-specificity.

Significance

Enhancers play a major role in regulating tissue-specific gene expression in higher eukaryotes, including angiosperms. While molecular characterization of enhancers has improved over the past years, identifying their target genes at the genome-wide scale remains challenging. Here, we integrate genomic, epigenomic and transcriptomic data to decipher the tissue-specific gene regulatory network controlled by enhancers at two different stages of maize leaf development. Using a systems biology approach, we identify transcription factor families regulating gene tissue-specific expression in husk and seedling leaves, and characterize the enhancers likely to be involved. We show that a large part of maize enhancers is derived from transposable elements, which can provide novel transcription factor binding sites crucial to the regulation of tissue-specific biological functions.
Can fMRI reveal the representation of syntactic structure in the brain?
Authors: Reddy Aniketh Janardhan , Wehbe Leila
Published: June 2020

While studying semantics in the brain, neuroscientists use two approaches. One is to identify areas that are correlated with semantic processing load. Another is to find areas that are predicted by the semantic representation of the stimulus words. However, in the domain of syntax, most studies have focused only on identifying areas correlated with syntactic processing load. One possible reason for this discrepancy is that representing syntactic structure in an embedding space such that it can be used to model brain activity is a non-trivial computational problem. Another possible reason is that it is unclear if the low signal-to-noise ratio of neuroimaging tools such as functional Magnetic Resonance Imaging (fMRI) can allow us to reveal correlates of complex (and perhaps subtle) syntactic representations. In this study, we propose novel multi-dimensional features that encode information about the syntactic structure of sentences. Using these features and fMRI recordings of participants reading a natural text, we model the brain representation of syntax. First, we find that our syntactic structure-based features explain additional variance in the brain activity of various parts of the language system, even after controlling for complexity metrics that capture processing load. At the same time, we see that regions well-predicted by syntactic features are distributed in the language system and are not distinguishable from those processing semantics.
Chemical-genetic interrogation of RNA polymerase mutants reveals structure-function relationships and physiological tradeoffs
Authors: Shiver Anthony L. , Osadnik Hendrik , Peters Jason M. , Mooney Rachel A. , Wu Peter I. , Hu James C. , Landick Robert , Huang Kerwyn Casey , Gross Carol A.
Published: June 2020

The multi-subunit bacterial RNA polymerase (RNAP) and its associated regulators carry out transcription and integrate myriad regulatory signals. Numerous studies have interrogated the inner workings of RNAP, and mutations in genes encoding RNAP drive adaptation ofEscherichia colito many health- and industry-relevant environments, yet a paucity of systematic analyses has hampered our understanding of the fitness benefits and trade-offs from altering RNAP function. Here, we conduct a chemical-genetic analysis of a library of RNAP mutants. We discover phenotypes for non-essential insertions, show that clustering mutant phenotypes increases their predictive power for drawing functional inferences, and illuminate a connection between transcription and cell division. Our findings demonstrate that RNAP chemical-genetic interactions provide a general platform for interrogating structure-function relationshipsin vivoand for identifying physiological trade-offs of mutations, including those relevant for disease and biotechnology. This strategy should have broad utility for illuminating the role of other important protein complexes.
Exploring how institutions shape managerialist employment relations and work-life balance (WLB) challenges in Nigeria
Authors: Nwagbara Uzoechi
Published: June 2020

Purpose

This study explores the nexus between institutions and managerialist employment relations and subsequent work-life balance (WLB) challenges for Nigerian employees. Through an exploratory approach, the paper investigates how institutions shape employment relations, which is characterised by systematic and normalised managerialist practices and lack of employee participation.

Design/methodology/approach

Relying on a qualitative, interpretive approach, this study explores the relationship between institutional pressures, managerialism and employment relations. 31 semi-structured interviews and nine focus group interviews data was used.

Findings

This paper found that institutions shape organisational practice, specifically employment relations and human resource management (HRM) practice generally through its normative tendency. The study also found that although managerialist employment relations leads to WLB challenges, Nigeria's unique context aggravates this situation constituting serious WLB challenges for workers.

Research limitations/implications

Researches dealing with the relationship between managerialism, employment relations and WLB are largely underdeveloped and under-theorised. HRM phenomena such as unhappy workforce, stress, lack of flexibility, burnout, turnover and turnover intention, associated with management practice, have major implications for engagement procedures and HRM strategies. However, the sample size used potentially limits generalisation including its qualitative approach.

Originality/value

This study contributes to the dearth of researches focusing on employer–employee relationship quality as a precursor to WLB challenges and a mediator between managerialist employment relations and WLB challenges. Additionally, the study contributes to the burgeoning WLB discourse from developing countries perspective, which is understudied. It also sheds light on how Nigeria's unique context can bring new insights into the nascent WLB discourse and its associated HRM practices.
Judicial exclusivity in actions against public authorities: civil procedure rule, O’Reilly and human rights
Authors: Ng May Yee
Published: June 2020

Purpose

This paper aims to provide an account of the legal development concerning civilian right to pursue legal action against public authorities. Review includes historical recap of the state of law practiced prior to 1977 and the decision in the case of O’Reilly that forcefully limit individual’s right to bring action. Despite its blatant disregard of the relevant statute, the O’Reilly decision remains a valid precedent. The essay then considers subsequent law reform and the effect of the Human Rights Act 1998 in limiting the applicability of the O’Reilly principle. The essay aims to benefit law students and non-legal lay person.

Design/methodology/approach

The paper adopts a hermeneutics positivism approach in considering relevant case laws that is precedent to the matter under discussion. Thereupon, an interpretivism approach is applied to examine subsequent reforms and its impact on civilian right to seek justice.

Findings

Judicial exclusivity restrains right to seek justice, but is it not totally discredited due to public policy. UK membership in the EU is an obstacle to judicial sovereignty, but it is also an avenue to dilute exclusivity.

Social implications

This paper is presented in a simple easy-to-understand form that enable lay-person to understand the current state of law in matters concerning public law violation by public authorities and avenues available to them.

Originality/value

The paper contributes to reinforce understanding on the conflict between common law and statute, and current state of law concerning individual’s right to access to the court of law in cases related to public laws and public authorities.
Empirical evidence on the profitability of momentum trading strategies using ETFs
Authors: Yu Susana , Webb Gwendolyn
Published: June 2020

Purpose

We extend empirical evidence on the profitability of momentum trading to the realm of plain-equity ETFs.

Design/methodology/approach

We employ several ranking measures used in prior research, and for each we apply a traditional ranking based on total return, and a variation based only on the capital gain/loss portion of return.

Findings

While we find that past momentum is not a strong predictor of future performance in our overall sample period, 2007 to June 2018, we find that the percent off 52-week high price results in positive performance in the recovery years following the financial crisis of 2008–2009.

Research limitations/implications

Our study is limited by the availability of ETF experience and data, and our test period covers just 2007 through June 2018. This period includes the financial crisis of 2008–2009, which previous research finding is associated with the momentum strategy's loss of profitability. When we exclude that period, we find evidence of a profitable momentum strategy based on the measure of percent off 52-week high price, enabling us to reject the null hypothesis that the momentum trading strategy is no longer profitable.

Practical implications

It is profitable based on both return measures used in the rankings. Our finding of a profitable momentum trading strategy suggests that the null hypothesis that the momentum strategy is no longer profitable can be rejected.

Originality/value

While perhaps not so strong as to reject the efficient markets hypothesis fully, our empirical findings are more consistent with a behavioral explanation and a market inefficiency. In view of the relative ease and low transactional costs of trading in ETFs, the markets have yet another opportunity to recognize an apparent mispricing and employ arbitrage based on it. To the extent that the relative ease of trading in ETFs makes momentum strategies easier to employ, the momentum anomaly might still be expected to disappear in an efficient market.
Scalp microbiota in members of a Japanese high school judo team including Trichophyton tonsurans carriers
Authors: Futatsuya Taketoshi , Ushigami Tsuyoshi , Nomura Fumie , Anzawa Kazushi , Mochizuki Takashi , Cho Otomi , Sugita Takashi
Published: June 2020

Trichophyton tonsurans is a major causative fungus of human dermatophytosis, which has been isolated from contact sport players in Japan. The microbiome in the scalp of judoists with or without T. tonsurans infection was analyzed to investigate the correlation between T. tonsurans infection and microbiome profile. Among 30 members of the same judo team in a high school, samples were collected by scrubbing their scalp with shampoo hairbrushes; then, DNA was extracted directly from the obtained scales. Twenty‐seven datasets were subjects for microbiome analysis and T. tonsurans was detected in six members (no T. tonsurans‐positive participants had scalp lesions). Regarding the fungal microbiome, Cyphellophora were more abundant in the T. tonsurans‐positive group (TP) than T. tonsurans‐negative group (TN) (P < 0.05). Regarding the Malassezia microbiome, Malassezia caprae were more abundant in TP than TN (P < 0.01). Regarding the bacterial microbiome, Lactococcus, Actinobacillus, Beijerinckiaceae and Xanthomonas were more abundant in TP than TN (P < 0.05). Also, the Shannon diversity index revealed no significant diversity between TP and TN, and 3‐D principal coordinate analysis revealed no clear separation between TP and TN. There was practically no difference in microbiome between TP and TN, indicating that T. tonsurans could colonize humans regardless of their original microbiome. T. tonsurans coexisted with other fungi and bacteria without affecting species diversity in asymptomatic carriers. To our knowledge, this is the first investigation of the correlation between T. tonsurans infection and microbiome profile.
Crossing extreme habitat boundaries: Jack‐of‐all‐trades facilitates invasion but is eroded by adaptation to a master‐of‐one
Authors: Ord Terry J. , Hundt Peter J.
Published: June 2020

The invasion of new environments can be a key instigator of adaptive diversification, but the likelihood of such invasions succeeding can depend on the attributes of would‐be invaders. Chief among these seems to be a generalist or ‘jack‐of‐all‐trades’ phenotype.

Yet, despite the obvious link between habitat transitions and adaptation, we know surprisingly little about how phenotypes that might initially allow taxa to transition between habitats subsequently evolve or influence post‐invasion differentiation.

We tested how a generalist phenotype of a broad diet and behavioural plasticity in marine blenny fish has facilitated the repeated invasion of extreme environments—particularly land—and how the conditions post‐invasion have impacted that generalist phenotype and associated trophic morphology.

Our data show that a wide diet and plasticity in being able to shift between environments freely have been instrumental in the progressive invasion of land by amphibious blennies. Once established, however, terrestrial blennies have experienced strong stabilizing selection for a restricted diet, little to no plasticity and a highly specialized morphology. Instead of promoting diversification, the invasion of land appears to offer only a limited niche for survival, constraining descendent blennies to a specific adaptive phenotype.

While our study supports the view that generalism facilitates invasion and that habitat transitions instigate adaptation, it also shows a generalist strategy is not optimal for successful establishment and new environments may offer fewer (not more) opportunities for diversification. This has broad implications for how taxa might be expected to respond or adapt to abrupt environmental change more generally.

A freeplain language summarycan be found within the Supporting Information of this article.