bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early-life stress facilitates the development of Alzheimer’s disease pathology via angiopathy
Authors: Tanaka Tomoko , Hirai Shinobu , Hosokawa Masato , Saito Takashi , Sakuma Hiroshi , Saido Takaomi , Hasegawa Masato , Okado Haruo 
Published: April 2020

AbstractBackgroundAlzheimer’s disease (AD), a progressive neurodegenerative disorder, is a serious social problem. Recently, several early-life factors have been associated with an increased risk of a clinical diagnosis of AD.MethodsWe investigated the involvement of early-life stress in AD pathogenesis using heterozygous the amyloid precursor protein (APP) mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. Maternal separation was used as an animal paradigm for early-life stress. Object location and fear conditioning tests were performed to measure cognitive functions, in addition to biochemical tests. Immunohistochemical analyses were performed after the behavioral tests.ResultsWe found that maternal-separatedAppwt/wtmice showed narrowing of vessels and decreased pericyte coverage of capillaries in prefrontal cortex, while maternal-separatedAppNL-G-F/wtmice additionally showed impairment of cognitive function, and earlier formation of Aβ plaques and disruption of the blood–brain barrier. Severe activation of microglia was detected in the maternal-separatedAppNL-G-F/wtmice and maternal-separatedAppwt/wtmice. At the early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separatedAppNL-G-F/wtmice and maternal-separatedAppwt/wtmice, as well as morphological changes in the microglia of the non-maternal-separatedAppNL-G-F/wtmice.ConclusionsMicroglia activation induced by maternal separation in combination with the APP mutation may impairs the vascular system, leading to AD progression. These findings therefore suggest that maternal separation causes early induction of AD pathology via angiopathy.
Evolutionary analysis of the LORELEI gene family in angiosperms reveals regulatory subfunctionalization
Authors: Noble Jennifer A. , Bielski Nicholas V. , Liu Ming-Che James , DeFalco Thomas A. , Stegmann Martin , Nelson Andrew D.L. , McNamara Kara , Sullivan Brooke , Dinh Khanhlinh K. , Khuu Nicholas , Hancock Sarah , Shiu Shin-Han , Zipfel Cyril , Cheung Alice Y. , Beilstein Mark A. , Palanivelu Ravishankar 
Published: April 2020

AbstractA signaling complex comprising members of the LORELEI (LRE)-LIKE GPI-anchored protein (LLG) andCatharanthus roseusRECEPTOR-LIKE KINASE 1-LIKE (CrRLK1L) families perceive RAPID ALKALINIZATION FACTOR (RALF) peptides and regulate growth, reproduction, immunity, and stress responses in Arabidopsis. Genes encoding these proteins are members of multi-gene families in most angiosperms and could generate thousands of signaling complex variants. However, the link(s) between expansion of these gene families and the functional diversification of this critical signaling complex as well as the evolutionary factors underlying the maintenance of gene duplicates remain unknown. Here, we investigatedLLGgene family evolution, function, and expression in angiosperms. We found thatLLGsin monocots and eudicots are descendants of a duplication early in angiosperm evolution and that both ancient and recentLLGduplicates are retained. Complementation and expression analysis showed that expression divergence ofLLGs(regulatory subfunctionalization), rather than functional divergence, explains the retention of paralogs in Brassicales. All but one extant monocot and eudicot species examined maintained anLLGcopy with preferential expression in male reproductive tissues, with the other duplicate copies showed highest levels of expression in female or vegetative tissues. Interestingly, the singleLLGcopy in Amborella (sister to all other angiosperms) is expressed vastly higher in male compared to female reproductive or vegetative tissues. Reconstruction of expression evolution showed that the highest inferred expression levels for the single copy ancestral angiospermLLGwas in male reproductive tissues. We propose that expression divergence played an important role in maintenance ofLLGduplicates in angiosperms.One Sentence SummaryExpression divergence played an important role in maintenance of two sub-groups ofLLGduplicates in angiosperms
Site-specific effects of neurosteroids on GABAAreceptor activation and desensitization
Authors: Sugasawa Yusuke , Cheng Wayland W. L. , Bracamontes John R. , Chen Zi-Wei , Wang Lei , Germann Allison L. , Pierce Spencer R. , Senneff Thomas C. , Krishnan Kathiresan , Reichert David E. , Covey Douglas F. , Akk Gustav , Evers Alex S. 
Published: April 2020

ABSTRACTThis study examines how site-specific binding to the three identified neurosteroid binding sites in the α1β3GABAAreceptor (GABAAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β3(+)–α1(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β3subunit, promoting receptor desensitization and the α1subunit promoting ligand-specific effects. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABAAR currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for site-specific and general neurosteroid antagonists. Collectively, these data show that differential occupancy and efficacy at three discrete neurosteroid binding sites determine whether a neurosteroid has potentiating, inhibitory, or competitive antagonist activity on GABAARs.
Optical TrkB activation in Parvalbumin interneurons regulates intrinsic states to orchestrate cortical plasticity
Authors: Winkel Frederike , Voigt Mathias B. , Didio Giuliano , Matéo Salomé , Jetsonen Elias , Pou Maria Llach , Steinzeig Anna , Ryazantseva Maria , Harkki Juliana , Englund Jonas , Khirug Stanislav , Rivera Claudio , Palva Satu , Taira Tomi , Lauri Sari E. , Umemori Juzoh , Castrén Eero 
Published: April 2020

AbstractActivation state of Parvalbumin (PV) interneurons regulates neuronal plasticity, driving the closure of developmental critical periods and alternating between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states are regulated through the activation of TrkB neurotrophin receptors. Activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing excitability of PV neurons. OptoTrkB activation induces changes in gene expression related to neuronal plasticity and excitability, and increases the phosphorylation of Kv3.1 channels. OptoTrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony and ocular dominance plasticity. Visual plasticity induced by fluoxetine was lost in mice lacking TrkB in PV neurons. Our data suggest a novel mechanism that dynamically regulates PV interneurons configuration state and orchestrates cortical networks during adulthood.Graphical Abstract
Improved freshwater macroinvertebrate detection from eDNA through minimized non-target amplification
Authors: Leese Florian , Sander Mandy , Buchner Dominik , Elbrecht Vasco , Haase Peter , Zizka Vera M.A. 
Published: April 2020

AbstractDNA metabarcoding of freshwater communities typically relies on PCR amplification of a fragment of the mitochondrial cytochrome c oxidase (COI) gene with degenerate primers. The advantage of COI is its taxonomic resolution and the availability of an extensive reference database. However, when universal primers are used on environmental DNA (eDNA) isolated from stream water, macroinvertebrate read and OTU numbers are typically “watered down”, i.e. diluted, compared to whole specimen ‘bulk samples’ due to greater co-amplification of abundant non-target taxa such as algae and bacteria. Because stream macroinvertebrate taxa are of prime importance for regulatory biomonitoring, more effective ways to capture their diversity via eDNA isolated from water are important. In this study, we aimed to improve macroinvertebrate assessment from eDNA by minimizing non-target amplification. Therefore, we generated data using universal primers BF2/BR2 throughout 15 months from a German Long-Term Ecological Research (LTER) site, the River Kinzig, to identify most abundant non-target taxa. Based on these data, we designed a new reverse primer (EPTDr2n) with 3’-specificity towards macrozoobenthic taxa and validated its specificityin silicotogether with universal forward primer fwhF2 using available data from GenBank and BOLD. We then performedin vitrotests using 20 eDNA samples taken in the Kinzig catchment. We found that the percentage of target reads was much higher for the new primer combination compared to two universal macrozoobenthic primer pairs, BF2/BR2 and fwhF2/fwhR2n (>99 % vs. 21.4 % and 41.25 %, respectively). Likewise, number of detected macroinvertebrate taxa was substantially higher (351 vs. 46 and 170, respectively) and exceeded the number of 257 taxa identified by expert taxonomists at nearby sites across two decades of sampling. While few taxa such as Turbellaria were not detected, we show that the optimized primer avoids the dilution problem and thus significantly improves macroinvertebrate detection for bioassessment and -monitoring.
TCGA Pan-Cancer genomic analysis of Alternative Lengthening of Telomeres (ALT) related genes
Authors: Armendáriz-Castillo Isaac , López-Cortés Andrés , García-Cárdenas Jennyfer , Guevara-Ramírez Patricia , Leone Paola E. , Pérez-Villa Andy , Yumiceba Verónica , Zambrano Ana K. , Guerrero Santiago , Paz-y-Miño César 
Published: April 2020

AbstractTelomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors have the ability to switch from a telomerase-dependent mechanism to ALT, in fact, the co-existence between telomerase and the ALT pathway have been observed in a variety of cancer types. Despite different elements in the ALT pathway have been uncovered, the molecular mechanism and other factors are still poorly understood, which difficult the detection and treatment of ALT-positive cells, which are known to present poor prognosis. Therefore, with the aim to identify potential molecular markers to be used in the study of ALT, we combined simplisticin silicoapproaches in 411 telomere maintenance (TM) genes which have been previously validated or predicted to be involved in the ALT pathway. In consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies (n=9,282) from The Cancer Genome Atlas in the cBioPortal and found 325,936 genomic alterations, being mRNA high and low the top alterations with 65,.8% and 10.7% respectively. Moreover, we analyzed the highest frequency means of genomics alterations, identified and proposed 20 genes, which are highly mutated and up and down regulated in the cancer studies and could be used for future analysis in the study of ALT. Finally, we made a protein-protein interaction network and enrichment analysis to obtain an insight into the main pathways these genes are involved. We could observe their role in main processes related to the ALT mechanism like homologous recombination, homology directed repair (HDR), HDR through homologous recombination and telomere maintenance and organization.. Overall, due to the lack of understanding of the molecular mechanisms and detection of ALT-positive cancers, we identified and proposed more molecular targets that can be used for expression analysis and additionalex vivoassays to validate them as new potential therapeutic markers in the study of the ALT mechanism.
The preservation of ancient DNA in archaeological fish bone
Authors: Ferrari Giada , Cuevas Angelica , Gondek-Wyrozemska Agata T. , Ballantyne Rachel , Kersten Oliver , Pálsdóttir Albína H. , van der Jagt Inge , Hufthammer Anne-Karin , Ystgaard Ingrid , Wickler Stephen , Bigelow Gerald F. , Harland Jennifer , Nicholson Rebecca , Orton David , Clavel Benoît , Boessenkool Sanne , Barrett James H. , Star Bastiaan 
Published: April 2020

AbstractThe field of ancient DNA is taxonomically dominated by studies focusing on mammals. This taxonomic bias limits our understanding of endogenous DNA preservation for vertebrate taxa with different bone physiology, such as teleost fish. In contrast to most mammalian bone, teleost bone is typically brittle, porous, lightweight and is characterized by a lack of bone remodeling during growth. Using high-throughput shotgun sequencing, we here investigate the preservation of DNA in a range of different bone elements from over 200 archaeological Atlantic cod (Gadus morhua) specimens from 38 sites in northern Europe, dating up to 8000 years before present. We observe that the majority of archaeological sites (79%) yield endogenous DNA, with 40% of sites providing samples that contain high levels (> 20%). Library preparation success and levels of endogenous DNA depend mainly on excavation site and pre-extraction laboratory treatment. The use of pre-extraction treatments lowers the rate of library success, although — if successful — the fraction of endogenous DNA can be improved by several orders of magnitude. This trade-off between library preparation success and levels of endogenous DNA allows for alternative extraction strategies depending on the requirements of down-stream analyses and research questions. Finally, we find that — in contrast to mammalian bones — different fish bone elements yield similar levels of endogenous DNA. Our results highlight the overall suitability of archaeological fish bone as a source for ancient DNA and provide novel evidence for a possible role of bone remodeling in the preservation of endogenous DNA across different classes of vertebrates.
Conformational stability and dynamics in crystals recapitulate protein behaviour in solution
Authors: Sala BM , Le Marchand T , Pintacuda G , Camilloni C , Natalello A , Ricagno S 
Published: April 2020

AbstractA growing body of evidences has established that in many cases proteins may preserve most of their function and flexibility in a crystalline environment, and several techniques are today capable to detect transiently-populated states of macromolecules in tightly packed lattices. Intriguingly, in the case of amyloidogenic precursors, the presence of these conformations (hidden to conventional crystallographic studies) can be correlated to the pathological fate of the native fold.It remains unclear, however, to which extent these minor conformations reflect the protein behaviour that is more commonly studied in solution. Here, we address this question by investigating some biophysical properties of a prototypical amyloidogenic system, β2-microglobulin (β2m) in solution and in microcrystalline state.By combining NMR chemical shifts with Molecular Dynamics (MD) simulations, we confirmed that conformational dynamics of β2m native state in the crystal lattice is in keeping with what observed in solution.A comparative study of protein stability in solution andin crystallois then carried out, monitoring the change in protein secondary structure at increasing temperature by Fourier transform infrared (FTIR) spectroscopy. The increased structural order of the crystalline state contributes to provide better resolved spectral components compared to those collected in solution and crucially, the crystalline samples display thermal stabilities in good agreement with the trend observed in solution.Overall, this work shows that protein stability and occurrence of pathological hidden states in crystals parallel their solution counterpart, confirming the interest of crystals as a platform for the biophysical characterisation of processes such as unfolding and aggregation.
Red light corrects neonicotinoid induced immunodeficiency and impaired respiration in poisoned bumblebees
Authors: Powner Michael B , Priestley Graham , Hogg Chris , Jeffery Glen 
Published: April 2020

AbstractNeonicotinoid pesticides undermine mitochondrial function in insects including bumblebees, reducing ATP, mobility and leading to death. They also reduce bumblebee immunocompetency leaving them vulnerable to pathogen attack. This undermines key pollinators critical in the agricultural economy. However, 670nm light exposure improves mitochondrial function undermined by age or disease, increasing respiratory chain efficiency, improving ATP production, mobility and survival in bumblebees and fruit flies. Here we show that 670nm restores immunocompetence, improving hemocyte counts and hemolymph anti-microbial action. Additionally, we measure whole body respirationin vivoin individual bumblebees revealing that it is a functional metric of both neonicotinoid impact and light induced mitochondrial protection. Critically we show that only 1 min 670nm exposure is sufficient to correct respiratory deficits induced by pesticide and restore normal immune ability. Longer exposures are not more effective. Further, single 1 min exposure protects respiration and immunity for approximately 3-6 days. Hence, 670nm impact is not dose dependent but switch like.These data provide a compelling rational for 670nm application to protect pollinators on which a major part of the agro economy is based and who are being challenged by aggressive pesticide application.
Fast and furious: host aggression modulates behaviour of brood parasites
Authors: Jelínek Václav , Šulc Michal , Štětková Gabriela , Honza Marcel 
Published: April 2020

ABSTRACTAvian brood parasites pose a serious threat for hosts, substantially reducing their fitness which selects for the evolution of host defences. A classic example of a host frontline defence is mobbing which frequently includes contact attacking of brood parasites. Here, we investigated how the nest defence of a very aggressive great reed warbler (Acrocephalus arundinaceus) host influences the speed of egg-laying and egg-removing behaviour of its brood parasite – the common cuckoo (Cuculus canorus). We video-recorded 168 brood parasitic events at 102 active host nests and found that cuckoos avoided host mobbing in only 62% of cases. If hosts spotted the cuckoo at their nests, they almost always attacked it (in 91 of 104 cases), however, such attacks only rarely and temporarily prevented cuckoos from parasitizing (11 additional cases). When attacked, cuckoos parasitized host nests significantly faster and left them immediately. However, when not attacked, cuckoos frequently stayed at or near the nest suggesting that host aggression, rather than the risk of being spotted, influences the speed of brood parasitism in this species. Further, we found that cuckoos performed egg-removing behaviour in all parasitic events without regard to host aggression. As a result, cuckoos removed at least one egg during all brood parasitism events except those when an egg slipped from their beaks and fell back into the nest (in 9 of 73 cases). This indicates that egg-removing behaviour is not costly for the common cuckoo and is an essential part of its parasitism strategy, widening understanding of this currently unexplained behaviour.
Identification of essential genes and fluconazole resistance genes inCandida glabrataby profiling ofHermestransposon insertions
Authors: Gale Andrew N. , Sakhawala Rima M. , Levitan Anton , Sharan Roded , Berman Judith , Timp Winston , Cunningham Kyle W. 
Published: April 2020

ABSTRACTWithin the budding yeasts, the opportunistic pathogenCandida glabrataand other members of theNakaseomycesclade have developed virulence traits independently from the CTG clade that includesCandida albicans. To begin exploring the genetic basis ofC. glabratavirulence and its innate resistance to antifungals, we launched theHermestransposon from a plasmid and obtained more than 500,000 different semi-random insertions throughout the genome. Using machine learning, we identify up to 1278 protein-encoding genes (25% of total) that cannot tolerate transposon insertions and are thus essential forC. glabratafitness in vitro. Interestingly, genes involved in mRNA splicing were less likely to be essential inC. glabratathan their orthologs inS. cerevisiae, whereas the opposite is true for genes involved in kinetochore function and chromosome segregation. Insertions in several known genes (e.g.PDR1,CDR1,PDR16,PDR17,UPC2A,DAP1) caused hypersensitivity to the first-line antifungal fluconazole, and we identify 12 additional genes that also contribute to innate fluconazole resistance (KGD1,KGD2,YHR045W, etc). Insertions in 200 other genes conferred significant resistance to fluconazole, two-thirds of which function in mitochondria and likely down-regulate Pdr1 expression or function. These findings show the utility of transposon insertion profiling in genome-wide forward-genetic investigations of fungal pathogens.IMPORTANCEPathogenic yeasts cause mucosal and systemic infections in millions of people each year. The innate resistance ofCandida glabratato fluconazole and its ability to acquire resistance to 2 other antifungals are contributing to its rise in incidence. Our understanding ofC. glabratabiology has been hampered by inefficient genetic and genomic tools. This study addresses those deficiencies by developing powerful transposon mutagenesis strategies for the first time in this pathogen. We identify nearly all essential genes ofC. glabratathat could be targeted for development of new antifungals. We generate large pools of random insertion mutants that can be easily monitoreden massewith deep sequencing, thus enabling identification of genes involved in any number of biological processes. We identify dozens of new genes that increase or decrease innate resistance of clinical isolate BG2 to fluconazole and provide resources for further exploration ofC. glabratagenetics and genomics.
Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish
Authors: Demy DL , Campanari ML , Munoz-Ruiz R , Durham HD , Gentil BJ , Kabashi E 
Published: April 2020

AbstractNeurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. Thede novoassembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologueneflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4andneflbE3).In vivoimaging showed thatneflbis crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.