bluuebunny/crossref_metadata_2025_split 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

ABSTRACTOxidative 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

ABSTRACTLoss 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

AbstractMultivalent 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 StatementIntrinsically 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

SummaryGrowth 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

AbstractVisual 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.
Remodeling mechanisms determine size distributions in developing retinal vasculature
Authors: Iizuka Osamu , Kawamura Shotaro , Tero Atsushi , Uemura Akiyoshi , Miura Takashi 
Published: June 2020

AbstractThe 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

AbstractLiquid-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

AbstractChickens, 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

AbstractWhile 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

AbstractThe 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

ABSTRACTCholesterol-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

AbstractThe 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

ABSTRACTHypothesisAsbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations.MethodsGenetically 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.ResultsInjection 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.ConclusionAsbestos-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

AbstractObesity 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

AbstractEcologists 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.