bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration
Authors: van Olst Lynn , Rodriguez-Mogeda Carla , Picon-Munoz Carmen , Kiljan Svenja , James Rachel E. , Kamermans Alwin , van der Pol Susanne M.A. , Knoop Lydian , Drost Evelien , Franssen Marc , Schenk Geert , Geurts Jeroen J.G. , Amor Sandra , Mazarakis Nicholas D. , van Horssen Jack , de Vries Helga E. , Reynolds Richard , Witte Maarten E. 
Published: September 2020

AbstractMeningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, contributing to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. Using extensive analysis of human post-mortem tissue, we identified two distinct microglial phenotypes, termed MS1 and MS2, in the cortex of progressive MS patients. These phenotypes differed in morphology and protein expression, but both associated with inflammation of the overlying meninges. We could replicate the MS-specific microglial phenotypes in a novelin vivorat model for progressive MS-like meningeal inflammation, with microglia present at 1 month post-induction resembling MS1 microglia whereas those at 2 months acquired an MS2-like phenotype. Interestingly, MS1 microglia were involved in presynaptic displacement and phagocytosis and associated with a relative sparing of neurons in the MS and animal cortex. In contrast, the presence of MS2 microglia coincided with substantial neuronal loss. Taken together, we uncovered that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Our data suggests that these phenotypes occur sequentially and that microglia may lose their protective properties over time, contributing to neuronal loss.
Pathogenic Mutations in the Kinesin-3 Motor KIF1A Diminish Force Generation and Movement Through Allosteric Mechanisms
Authors: Budaitis Breane G. , Jariwala Shashank , Rao Lu , Sept David , Verhey Kristen J. , Gennerich Arne 
Published: September 2020

ABSTRACTThe kinesin-3 motor KIF1A functions in neurons where its fast and superprocessive motility is thought to be critical for long-distance transport. However, little is known about the force-generating properties of kinesin-3 motors. Using optical tweezers, we demonstrate that KIF1A and itsC. eleganshomolog UNC-104 undergo force-dependent detachments at ~3 pN and then rapidly reattach to the microtubule to resume motion, resulting in a sawtooth pattern of clustered force generation events that is unique among the kinesin superfamily. Whereas UNC-104 motors stall before detaching, KIF1A motors do not. To examine the mechanism of KIF1A force generation, we introduced mutations linked to human neurodevelopmental disorders, V8M and Y89D, based on their location in structural elements required for force generation in kinesin-1. Molecular dynamics simulations predict that the V8M and Y89D mutations impair docking of the N-terminal (β9) or C-terminal (β10) portions of the neck linker, respectively, to the KIF1A motor domain. Indeed, both mutations dramatically impair force generation of KIF1A but not the motor’s ability to rapidly reattach to the microtubule track. Homodimeric and heterodimeric mutant motors also display decreased velocities, run lengths, and landing rates and homodimeric Y89D motors exhibit a higher frequency of non-productive, diffusive events along the microtubule. In cells, cargo transport by the mutant motors is delayed. Our work demonstrates the importance of the neck linker in the force generation of kinesin-3 motors and advances our understanding of how mutations in the kinesin motor domain can manifest in disease.
The microbiome affects liver sphingolipids and plasma fatty acids in a murine model of the Western diet based on soybean oil
Authors: Di Rienzi Sara C. , Johnson Elizabeth L. , Waters Jillian L. , Kennedy Elizabeth A. , Jacobson Juliet , Lawrence Peter , Wang Dong Hao , Worgall Tilla S. , Brenna J. Thomas , Ley Ruth E. 
Published: September 2020

AbstractStudies in mice using germfree animals as controls for microbial colonization have shown that the gut microbiome mediates diet-induced obesity. Such studies use diets rich in saturated fat, however, Western diets in the USA are enriched in soybean oil, composed of unsaturated fatty acids (FAs), either linoleic or oleic acid. Here we addressed whether the microbiome is a variable in fat metabolism in mice on a soybean oil diet. We used conventionally-raised, low-germ, and germfree mice fed for 10 weeks diets either high (HF) or low (LF) in high-linoleic-acid soybean oil as the sole source of fat. All mice, including germfree, gained relative fat weight and consumed more calories on the HF versus LF soybean oil diet. Plasma fatty acid levels were generally dependent on diet, with microbial colonization status affectingiso-C18:0, C20:3n-6, C14:0, and C15:0 levels. Colonization status, but not diet, impacted levels of liver sphingolipids including ceramides, sphingomyelins, and sphinganine. Our results confirm that absorbed fatty acids are mainly a reflection of the diet, and show that microbial colonization influences liver sphingolipid pools.
Genome sequence of the oyster mushroomPleurotus ostreatusstrain PC9
Authors: Lee Yi-Yun , de Ulzurrun Guillermo Vidal-Diez , Schwarz Erich M. , Stajich Jason E. , Hsueh Yen-Ping 
Published: September 2020

AbstractThe oyster mushroomPleurotus ostreatusis a basidiomycete commonly found in the rotten wood and it is one of the most cultivated edible mushrooms globally.P. ostreatusis also a carnivorous fungus, which can paralyze and kill nematodes within minutes. However, the molecular mechanisms of the predator-prey interactions betweenP. ostreatusand nematodes remain unclear. PC9 and PC15 are two model strains ofP. ostreatusand the genomes of both strains have been sequenced and deposited at the Joint Genome Institute (JGI). These two monokaryotic strains exhibit dramatic differences in growth, but because PC9 grows more robustly in laboratory conditions, it has become the strain of choice for many studies. Despite the fact that PC9 is the common strain for investigation, its genome is fragmentary and incomplete relative to that of PC15. To overcome this problem, we used PacBio long reads and Illumina sequencing to assemble and polish a more integrated genome for PC9. Our PC9 genome assembly, distributed across 17 scaffolds, is highly contiguous and includes six telomere-to-telomere scaffolds, dramatically improving the genome quality. We believe that our PC9 genome resource will be useful to the fungal research community investigating various aspects ofP. ostreatusbiology.
Time scales of mixing in an imperforate scleractinian coelenteron
Authors: Williams Sara D. , Patterson Mark R. 
Published: September 2020

AbstractCoelentera are the largest components by volume in the gastrovascular system connecting polyps in a scleractinian colony. Thus to understand colony connectivity which is predicted to affect corals’ response to environmental change, we must first describe the dynamics inside these gastric cavities of individual polyps. We determined key time scales of mixing in coelentera by using microelectrodes to measure oxygen concentration after a light-to-dark transition in three polyps each of three colonies ofMontastraea cavernosain the laboratory. The gastrovascular system was modeled as an electrical network where voltage represents oxygen concentration, current represents oxygen flux, capacitors represent volume compartments, and resistors represent impedance to oxygen flux. The time constant of mixing, defined as the time needed for the system to disperse 63.2% of the fluid in the coelenteron, was determined from the oxygen dynamics in the coelenteron as modeled by a resistor-capacitor network. Time constants were on the order of three minutes and oxygen dynamics were well fit by the model prediction. However, as polyps depleted oxygen, we observed small magnitude (~ 0.1 ppm), high-frequency fluctuations in oxygen concentration. A power spectral density analysis identified two time scales of high-frequency mixing in the coelenteron. The greatest variance occurred at a period of 48.3 ± 2.8 seconds, with a secondary peak seen at 35.9 ± 2.3 seconds. The microenvironment within polyps ofM. cavernosacan respond as fast or faster than their external environment can fluctuate, thus scleractinian polyps have the capacity to mediate their response to changing environmental conditions.
Effects of age and hearing loss on perceptual and physiological measures of temporal envelope processing and spatial release from speech-on-speech masking
Authors: Patro Chhayakanta , Kreft Heather A. , Wojtczak Magdalena 
Published: September 2020

AbstractOlder adults often experience difficulties understanding speech in adverse listening conditions. These difficulties are partially attributed to auditory temporal-processing deficits associated with aging even in the absence of hearing loss. The aim of this study was to assess effects of age and hearing loss on temporal envelope processing and speech-on-speech masking. Listeners with normal and near-normal hearing across a wide age range (20 to 66 years) were tested using a series of psychophysical (amplitude-modulation detection, gap detection, and interaural-envelope-phase discrimination), physiological (electroencephalographic envelope-following responses), speech perception (spatial release from masking), and cognitive (processing speed) measures. Results showed that: (i) psychophysical measures of monaural and binaural envelope processing and neural measures of envelope processing are not affected by aging after accounting for audiometric hearing loss, (ii) behavioral gap-detection thresholds decline with age, (iii) aging results in a reduction of spatial release from masking, even as speech intensity is amplified in the region of hearing loss, (iv) aging is associated with poorer measures of cognitive function. Although age significantly contributed to a decline in spatial release from speech-on-speech masking, individual differences in envelope processing and in scores from nonauditory cognitive tests used in this study were not significant predictors of speech performance.HighlightsAge per se does not affect psychophysical and physiological measures of monaural amplitude-modulation processing.Age does not affect the ability to detect interaural disparities in envelope timing between the ears.Gap detection thresholds degrades with age even after hearing thresholds are statistically accounted for.Age, independent of hearing thresholds, can substantially reduce spatial release from masking.Cognitive ability declines with age. However, such declines do not necessarily cause deficits in spatial release from masking.
Phylo-geo-network and haplogroup analysis of 611 novel Coronavirus (nCov-2019) genomes from India
Authors: Laskar Rezwanuzzaman , Ali Safdar 
Published: September 2020

AbstractThe novel Coronavirus from Wuhan China discovered in December 2019 (nCOV-2019) has since developed into a global epidemic with major concerns about the possibility of the virus evolving into something even more sinister. In the present study we constructed the phylo-geo-network of nCOV-2019 genomes from across India to understand the viral evolution in the country. A total of 611 full length genomes were extracted from different states of India from the EpiCov repository of GISAID initiative and NCBI. Their alignment uncovered 270 parsimony informative sites. Further, 339 genomes were divided into 51 haplogroups. The network revealed the core haplogroup as that of reference sequence NC_045512.2 (Haplogroup A1) with 157 identical sequences present across 16 states. The rest were having not more than ten identical sequences across not more than three locations. Interestingly, some locations with fewer samples have more haplogroups and most haplogroups (41) are localized exclusively to any one state only, suggesting the local evolution of viruses. The two most common lineages are B6 and B1 (Pangolin) whereas clade A2a (Covidex) appears to be the most predominant in India. However, since the pandemic is still emerging, the final outcome will be clear later only.
Is there a role for the RNA-binding protein LARP1 in β-cells?
Authors: Werneck-de-Castro Joao Pedro , Peçanha Flavia Leticia Martins , Silvestre Diego , Bernal-Mizrachi Ernesto 
Published: September 2020

ABSTRACTMechanistic target of rapamycin complex 1 (mTORC1) is a cellular rheostat linking nutrient availability and growth factor to cellular protein translation. In pancreatic insulin secreting β-cells, mTORC1 deficiency or chronic hyperactivation leads to diabetes. mTORC1 complexes with La-related protein 1 (LARP1) to specifically regulate the expression of 5’ terminal oligopyrimidine tract (5’TOP) mRNAs which encode proteins of the translation machinery and ribosome biogenesis. We aimed to investigate the role played by LARP1 in β-cellsin vivo. Here we show that LARP1 is the most expressed LARP in mouse islets and human β-cells, being 2-4-fold more abundant than LARP1B, a member of the family that also interacts with mTORC1. Interestingly, β-cells from diabetic patients have higher LARP1 and LARP1B expression suggesting greater protein translation. These studies led us to generate a conditional LARP1 knockout mouse in β-cells (β-Larp1KOmice). These mice exhibit normal levels of all LARP family members includingLarp1B, Larp4, Larp6andLarp7. We did not observe any difference between control andβ-Larp1KOmale mice in body weight gain, glucose levels and glucose tolerance at 8, 14 and 44 weeks of age. Femaleβ-Larp1KOmice also performed normally during the glucose tolerance test. We then challenged theβ-Larp1KOmice with high fat (HFD) or high branched-chain amino acid (BCAA) diets. During the course of 8 weeks in HFD,β-Larp1KOand control mice had similar weight gain and did not show alterations in glucose homeostasis compared to control littermates. BCAA did not impair glucose metabolism up to 8 weeks of diet challenge. However, glucose tolerance was slightly impaired in theβ-Larp1KOmice at 16 weeks under BCAA diet. In conclusion, LARP1 is the most abundant LARP in mouse islets and human β-cells and it is upregulated in diabetic subjects. While the lack of LARP1 specifically in β-cells did not alter glucose homeostasis in basal conditions, long-term high branched-chain amino acid feeding could impair glucose tolerance.
Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation
Authors: Hou Xiaowei , Outhwaite Ian R. , Pedi Leanne , Long Stephen Barstow 
Published: September 2020

AbstractThe calcium release-activated calcium channel Orai regulates Ca2+entry into non-excitable cells and is required for proper immune function. The channel typically opens following the release of Ca2+from the endoplasmic reticulum. Certain pathologic mutations render the channel constitutively open. Here, using one such mutation (H206A), we present a cryo-EM structure of Orai fromDrosophila melanogasterin an open conformation at 3.3 Å resolution. Comparison with previous closed structures reveals that opening occurs through the outward movements of M1 helices that dilate the central pore. Repositionings of a ring of phenylalanine residues (F171) expose previously shielded glycine residues (G170) to the channel pore, despite the absence of significant rotational movement of the associated pore-lining helices. This phenylalanine ring and two rings of flanking hydrophobic amino acids act as a hydrophobic gate to control ion permeation. Extracellular M1-M2 turrets, not evident from previous Orai structures, form an electronegative pore entrance.Single sentence summaryA structure of the Ca2+channel Orai in an open conformation provides insight into the opening mechanism of the channel and its role in regulating selective Ca2+entry into immune and other non-excitable cells.
MecCog: A knowledge representation framework for genetic disease mechanism
Authors: Kundu Kunal , Darden Lindley , Moult John 
Published: September 2020

ABSTRACTMotivationExperimental findings on genetic disease mechanisms are scattered throughout the literature and represented in many ways, including unstructured text, cartoons, pathway diagrams, and network graphs. Integration and structuring of such mechanistic information will greatly enhance its utility.ResultsMecCog is a graphical framework for building integrated representations (mechanism schemas) of mechanisms by which a genetic variant causes a disease phenotype. A MecCog mechanism schema displays the propagation of system perturbations across stages of biological organization, using graphical notations to symbolize perturbed entities and activities, hyperlinked evidence tagging, a mechanism ontology, and depiction of knowledge gaps, ambiguities, and uncertainties. The web platform enables a user to construct, store, publish, browse, query, and comment on schemas. MecCog facilitates the identification of potential biomarkers, therapeutic intervention sites, and critical future experiments.Availability and ImplementationThe MecCog framework is freely available athttp://www.meccog.org.Contactjmoult@umd.eduSupplementary informationSupplementary material is available atBioinformaticsonline.
Comparative genomics ofClostridiumspecies associated with vacuum-packed meat spoilage
Authors: Palevich Nikola , Palevich Faith P. , Maclean Paul H. , Altermann Eric , Gardner Amanda , Burgess Sara , Mills John , Brightwell Gale 
Published: September 2020

ABSTRACTBacterial species belonging to theClostridiumgenera have been recognized as causative agents of blown pack spoilage (BPS) in vacuum packed meat products. Whole-genome sequencing of six New Zealand psychrotolerantClostridiumisolates derived from three meat production animal types and their environments was performed to examine their roles in BPS. Comparative genome analyses have provided insight into the genomic diversity and physiology of these bacteria and dividesClostridiainto two separate species clusters. BPS-associatedClostridiaencode a large and diverse spectrum of degradative carbohydrate-active enzymes (CAZymes). In total, 516 glycoside hydrolases (GHs), 93 carbohydrate esterases (CEs), 21 polysaccharide lyases (PLs), 434 glycosyl transferases (GTs) and 211 carbohydrate-binding protein modules (CBM) with predicted activities involved in the breakdown and transport of carbohydrates were identified.Clostridiagenomes have different patterns of CAZyme families and vary greatly in the number of genes within each CAZy category, suggesting some level of functional redundancy. These results suggest that BPS-associatedClostridiaoccupy similar environmental niches but apply different carbohydrate metabolism strategies to be able to co-exist and cause meat spoilage.
Modeling multiple phenotypes in wheat using data-driven genomic exploratory factor analysis and Bayesian network learning
Authors: Momen Mehdi , Bhatta Madhav , Hussain Waseem , Yu Haipeng , Morota Gota 
Published: September 2020

AbstractInferring trait networks from a large volume of genetically correlated diverse phenotypes such as yield, architecture, and disease resistance can provide information on the manner in which complex phenotypes are interrelated. However, studies on statistical methods tailored to multi-dimensional phenotypes are limited, whereas numerous methods are available for evaluating the massive number of genetic markers. Factor analysis operates at the level of latent variables predicted to generate observed responses. The objectives of this study were to illustrate the manner in which data-driven exploratory factor analysis can map observed phenotypes into a smaller number of latent variables and infer a genomic latent factor network using 45 agro-morphological, disease, and grain mineral phenotypes measured in synthetic hexaploid wheat lines (Triticum Aestivum L.). In total, eight latent factors including grain yield, architecture, flag leaf-related traits, grain minerals, yellow rust, two types of stem rust, and leaf rust were identified as common sources of the observed phenotypes. The genetic component of the factor scores for each latent variable was fed into a Bayesian network to obtain a trait structure reflecting the genetic interdependency among traits. Three directed paths were consistently identified by two Bayesian network algorithms. Flag leaf-related traits influenced leaf rust, and yellow rust and stem rust influenced grain yield. Additional paths that were identified included flag leaf-related traits to minerals and minerals to architecture. This study shows that data-driven exploratory factor analysis can reveal smaller dimensional common latent phenotypes that are likely to give rise to numerous observed field phenotypes without relying on prior biological knowledge. The inferred genomic latent factor structure from the Bayesian network provides insights for plant breeding to simultaneously improve multiple traits, as an intervention on one trait will affect the values of focal phenotypes in an interrelated complex trait system.
Drosophila melanogasteras a model host to study arbovirus–vector interaction
Authors: Paingankar Mandar S. , Gokhale Mangesh D. , Deobagkar Deepti D. , Deobagkar Dileep N. 
Published: September 2020

ABSTRACTArboviruses cause the most devastating diseases in humans and animals worldwide. Several hundred arbovirus are transmitted by mosquitoes, sand flies or ticks and are responsible for more than million deaths annually. Development of a model system is essential to extrapolate the molecular events occurring during infection in the human and mosquito host. Virus overlay protein binding assay (VOPBA) combined with MALDI TOF/TOF MS revealed that Dengue-2 virus (DENV-2) exploits similar protein molecules inDrosophila melanogasterandAedes aegyptifor its infection. Furthermore, the virus susceptibility studies revealed that DENV-2 could propagate inD. melanogaster, and DENV-2 produced in fruit fly is equally infectious toD. melanogasterandAe. aegypti. Additionally, real time PCR analysis revealed that RNAi coupled with JAK-STAT and Toll pathway constitutes an effector mechanism to control the DENV-2 infection in flies. These observations point out thatD. melanogasterharbors all necessary machineries to support the growth of arboviruses. With the availability of well-established techniques for genetic and developmental manipulations,D. melanogaster, offers itself as the potential model system for the study of arbovirus-vector interactions.
All-Trans Retinoic Acid induces synaptic plasticity in human cortical neurons
Authors: Lenz Maximilian , Kruse Pia , Eichler Amelie , Muellerleile Julia , Straehle Jakob , Jedlicka Peter , Beck Jürgen , Deller Thomas , Vlachos Andreas 
Published: September 2020

ABSTRACTA defining feature of the brain is its ability to adapt structural and functional properties of synaptic contacts in an experience-dependent manner. In the human cortex direct experimental evidence for synaptic plasticity is currently missing. Here, we probed plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid, which has been suggested as medication for the treatment of neuropsychiatric disorders, e.g., Alzheimer’s disease. Our experiments demonstrate coordinated structural and functional changes of excitatory synapses of superficial (layer 2/3) pyramidal neurons in the presence of all-trans retinoic acid. This synaptic adaptation is accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and requires mRNA-translation. We conclude that all-trans retinoic acid is a potent mediator of synaptic plasticity in the adult human cortex.