bluuebunny/crossref_metadata_2025_split huggingface dataset:
End-to-end Bayesian analysis of14C dates reveals new insights into lowland Maya demography
Authors: Price Michael Holton , Capriles José M. , Hoggarth Julie A. , Bocinsky Kyle , Ebert Claire E. , Jones James Holland 
Published: July 2020

ABSTRACTArchaeologists and demographers increasingly employ aggregations of published radiocarbon (14C) dates as demographic proxies summarizing changes in human activity in past societies. Presently, summed probability densities (SPDs) of calibrated radiocarbon dates are the dominant method of using14C dates to reconstruct demographic trends. Unfortunately, SPDs are incapable of converging on their true generating distributions even as the number of observations gets large. To overcome this problem, we propose a more principled alternative that combines finite mixture models and Bayesian inference to identify the generating distribution of a set of radiocarbon dates. Numerical simulations and an assessment of the statistical identifiability of our method demonstrate that it correctly converges on the generating distribution. We apply this novel end-to-end Bayesian approach to reconstruct prehistoric Maya demographic growth using a recently compiled Mesoamerican radiocarbon database. Our results show that the Maya Lowlands experienced a century of rapid growth rates (1%) during the Late Classic, followed by a rapid decrease in population during the Terminal Classic, and a subsequent more-modest resurgence in population during the Postclassic. Additionally, a detailed population reconstruction of the important political center of Tikal verifies that slow population growth between the Preclassic and Early Classic gave pace to rapid growth starting around AD 500 and peaking at the beginning of the eight century. Our proposed method verifies previous reconstructions based on settlement patterns and ceramics, but with far more precise time-resolution and characterization of uncertainty than has been possible.
Microchip based microrheology via Acoustic Force Spectroscopy shows that endothelial cell mechanics follows a fractional viscoelastic model
Authors: Nguyen Alfred , Brandt Matthias , Betz Timo 
Published: July 2020

AbstractActive microrheology is one of the main methods to determine the mechanical properties of cells and tissue, and the modelling of the viscoelastic properties of cells and tissue is under heavy debate with many competing approaches. Most experimental methods of active microrheology such as optical tweezers or atomic force microscopy based approaches rely on single cell measurements, and thus suffer from a low throughput. Here, we present a novel method for cell based microrheology using acoustic forces which allows multiplexed measurements of several cells in parallel. Acoustic Force Spectroscopy (AFS) is used to generate multi-oscillatory forces in the range of pN-nN on particles attached to primary human umbilical vein endothelial cells (HUVEC) cultivated inside a microfluidic chip. While the AFS was introduced as a single-molecule technique to measure mechanochemical properties of biomolecules, we exploit the AFS to measure the dynamic viscoelastic properties of cells exposed to different conditions, such as flow shear stresses or drug injections. By controlling the force and measuring the position of the particle, the complex shear modulusG*(ω) can be measured continuously over several hours. The resulting power-law shear moduli are consistent with fractional viscoelastic models. In our experiments we confirm a decrease in shear modulus after perturbing the actin cytoskeleton via cytochalasin B. This effect was reversible after washing out the drug. Although these measurements are possible, we provide critical information regarding the AFS as a measurement tool showing its capabilities and limitations. A key result is that for performing viscoelastic measurements with the AFS, a thorough calibration and careful data analysis is crucial, for which we provide protocols and guidelines.
Two- and three-dimensional tracking ofMFA2mRNA molecules in mating yeast
Authors: Geva Polina , Komoshvili Konstantin , Liberman-Aronov Stella 
Published: July 2020

AbstractIntracellular mRNA transport contributes to the spatio-temporal regulation of mRNA function and localized translation. In the budding yeast,Saccharomyces cerevisiae, asymmetric mRNA transport localizes ∼30 specific mRNAs including those encoding polarity and secretion factors, to the bud tip. The underlying process involves RNA binding proteins (RBPs), molecular motors, processing bodies (PBs), and the actin cytoskeleton. Recently, pheromone a-factor expression in mating yeast was discovered to depend upon proper localization of its mRNA,MFA2.MFA2mRNAs in conjunction with PBs cluster at the shmoo tip to form “mating bodies”, from which a-factor is locally expressed. The mechanism ensuring the correct targeting of mRNA to the shmoo tip is poorly understood.Here we analyzed the kinetics and trajectories ofMFA2mRNA transport in living, alpha-factor treated yeast. Two-(2D) and three-dimensional (3D) analyses allowed us to reconstruct the granule tracks and estimate granule velocities. Tracking analysis of singleMFA2mRNA granules, labeled using a fluorescent aptamer system, demonstrated three types movement: vibrational, oscillatory and translocational. The mRNA granule transport was complex; a granule could change its movement behavior and composition during its journey to the shmoo. Processing body assembly and the actin-based motor, Myo4p, were involved in movement ofMFA2mRNA to the shmoo, but neither was required, indicating that multiple mechanisms for translocation were at play. Our visualization studies present a dynamic view of the localization mechanism in shmoo-bearing cells.
Maternal immune activation during pregnancy alters early neurobehavioral development in nonhuman primate offspring
Authors: Vlasova Roza M. , Iosif Ana-Maria , Ryan Amy M. , Murai Takeshi , Lesh Tyler A. , Rowland Douglas J. , Bennett Jeffrey , Hogrefe Casey E. , Maddock Richard J. , Gandal Michael J. , Geschwind Daniel H. , Schumann Cynthia M. , Van de Water Judy , McAllister A. Kimberley , Carter Cameron S. , Styner Martin A. , Amaral David G. , Bauman Melissa D. 
Published: July 2020

ABSTRACTBackgroundHuman epidemiologic studies have implicated exposure to infectious or inflammatory insults during gestation in the etiology of neurodevelopmental disorders. Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior development in offspring. The nonhuman primate MIA model provides an opportunity to maximize the translational utility of this model in a species more closely related to humans.MethodsHere we evaluate the effects of MIA on brain and behavioral development in the rhesus monkey (Macaca mulatta). A modified form of the viral mimic, Polyinosinic-polycytidylic acid (PolyIC), was delivered to pregnant rhesus monkeys (n=14) in the late first trimester to stimulate a maternal immune response. Control dams received saline injections at the same gestational time points (n=10) or were untreated (n=4).ResultsMIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature and inflammatory cytokines. MIA-exposed offspring developed species typical milestones and demonstrate subtle changes in early in social development. However, magnetic resonance imaging demonstrated significant gray matter volume reductions in prefrontal and frontal cortices at 6, 12 and 24 months of age.ConclusionsThese findings provide new insights into the emergence of neuropathology in MIA-exposed primates and have implications for the pathophysiology of human psychiatric disorders associated with maternal gestational infection.
Global reinforcement of DNA methylation through enhancement of RNA-directed DNA methylation ensures sexual reproduction in rice
Authors: Wang Lili , Zeng Longjun , Zheng Kezhi , Zhu Tianxin , Yin Yumeng , Xu Dachao , Zhan Huadong , Wu Yufeng , Yang Dong-Lei 
Published: July 2020

AbstractDNA methylation is an important epigenetic mark that regulates the expression of genes and transposons. RNA-directed DNA methylation (RdDM) is the main molecular pathway responsible forde novoDNA methylation in plants. In Arabidopsis, however, mutations in RdDM genes cause no visible developmental defects, which raising the question of the biological significance of RdDM in plant development. Here, we isolated and clonedFive Elements Mountain 1(FEM1), which encodes an RNA-dependent RNA polymerase. Mutation inFEM1substantially decreased genome-wide CHH methylation levels and abolished the accumulation of 24-nt small interfering RNAs. Moreover, male and female reproductive development was disturbed, which led to the sterility offem1mutants. In wild-type (WT) plants but not infem1mutants, genome-wide CHH DNA methylation levels were greater in panicles, stamens, and pistils than in seedlings. The global increase of methylation in reproductive organs of the WT was attributed to enhancement of RdDM activity including FEM1 activity. More than half of all encoding genes in the rice genome overlapped with hypermethylated regions in the sexual organs of the WT, and many of them appear to be directly regulated by an increase in DNA methylation.Our results demonstrate that a global increase of DNA methylation through enhancement of RdDM activity in reproductive organs ensures sexual reproduction of rice.
Persistence: Using Protein Turnover to Expand the Applications of Transcriptomics
Authors: Smail Marissa A. , Reigle James K. , McCullumsmith Robert E. 
Published: July 2020

ABSTRACTOne of the major issues with RNA sequencing is the lack of reproducibility between RNA and protein expression. Transcriptomics offers a holistic view of the molecular landscape of a tissue at an RNA level. However, RNA and protein expression are often at odds when measured in the same sample, raising the question whether or not changes in RNA expression translate to functional differences. This problem creates a need to devise a way to approximate protein abundance from transcriptomics data, in order to create a more complete picture of the functional landscape of a tissue. One additional measure that could be useful here is protein turnover or half-life. Once RNA is transcribed into protein, that protein can either be quickly degraded or remain in the cell for an extended period of time. The longer a protein’s half-life, the more influence it can have on its surroundings. Recently, a study used stable isotope labeling in mammals (SILAM) in combination with mass spectrometry to determine the turnover ratio of ∼2200 protein in mouse synaptosomes. This data offers a valuable opportunity to integrate protein turnover with RNA expression to gain deeper insight into the functional meaning of RNA expression changes. Here, we present the concept of this combination of protein turnover and RNA expression, which we coined as persistence. We then demonstrate the application of persistence using schizophrenia (SCZ) transcriptomics datasets. Calculating persistence for these datasets greatly improved our ability to predict protein expression from RNA expression. Furthermore, this approach successfully identified persistent genes and pathways known to have impactful changes in SCZ. These results suggest that persistence is a valuable metric for improving the functional insight that can be gained from transcriptomics data.
The attachment of Sso7d-like protein improves processivity and resistance to inhibitors of M-MuLV reverse transcriptase
Authors: Oscorbin Igor P. , Wong Pei Fong , Boyarskikh Ulyana A. , Khrapov Evgeny A. , Filipenko Maksim L. 
Published: July 2020

ABSTRACTReverse transcriptases, RTs, are a standard tool in both fundamental studies and diagnostics used for transcriptome profiling, virus RNA testing and other tasks. RTs should possess elevated temperature optimum, high thermal stability, processivity, and tolerance to contaminants originating from the biological substances under analysis or the purification reagents. Here, we have constructed a set of chimeric RTs, based on the combination of MuLV-RT and DNA-binding domains: the DNA-binding domain of DNA ligasePyrococcus abyssiand Sto7d protein, Sso7d counterpart, fromSulfolobus tokodaii. Chimeric RTs showed the same optimal temperature and the efficacy of terminal transferase reaction as the original M-MuLV RT. Processivity and the efficiency in cDNA synthesis of the chimeric RT with Sto7d at C-end were increased several-fold. The attachment of Sto7d enhanced the M-MuLV RT tolerance to the most common amplification inhibitors: NaCl, urea, guanidinium chloride, formamide, components of human whole blood, and human blood plasma. Thus, fusing M-MuLV RT with an additional domain resulted in more robust and efficient RTs.
Arrhythmogenesis as the failure of repolarization
Authors: Heitmann Stewart , Vandenberg Jamie I , Hill Adam P 
Published: July 2020

AbstractContemporary theories of cardiac fibrillation typically rely on the emergence of rotors to explain the transition from regular sinus rhythm to disordered electrophysiological activity. How those rotors spontaneously arise in the absence of re-entrant anatomical circuits is not fully understood. Here we propose a novel mechanism where arrhythmias are initiated by cardiac cells that fail to repolarize following a normal heartbeat. Those cells subsequently act as a focal ectopic source that drive the ensuing fibrillation. We used a simple computational model to investigate the impact of such cells in both homogeneous and heterogeneous excitable media. We found that heterogeneous media can tolerate a surprisingly large number of abnormal cells and still support normal rhythmic activity. At a critical limit the medium becomes chronically arrhythmogenic. Numerical analysis revealed that the critical threshold for arrhythmogenesis depends on both the strength of the coupling between cells and the extent to which the abnormal cells resist repolarization. Arrhythmogenesis was also found to emerge first at tissue boundaries where cells naturally have fewer neighbors to influence their behavior. These findings may explain why atrial fibrillation typically originates from the cuff of the pulmonary vein.Author summaryCardiac fibrillation is a medical condition where normal heart function is compromised as electrical activity becomes disordered. How fibrillation arises spontaneously is not fully understood. It is generally thought to be triggered by premature depolarization of the cardiac action potential in one or more cells. Those premature beats, known as early-afterdepolarizations, subsequently initiate a self-sustaining rotor in the otherwise normal heart tissue. In this study, we propose an alternative mechanism whereby arrhythmias are initiated by cardiac cells that fail to repolarize of their own accord but still operate normally when embedded in functional heart tissue. We find that such cells can act as focal ectopic sources under appropriate conditions of inter-cellular coupling. Moreover, cells on natural tissue boundaries are more susceptible to arrhythmia because they are coupled to fewer cells. This may explain why the pulmonary vein is often implicated as a source of atrial fibrillation.
Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation
Authors: Queval Christophe J. , Fearns Antony , Botella Laure , Smyth Alicia , Schnettger Laura , Mitermite Morgane , Wooff Esen , Villarreal-Ramos Bernardo , Garcia-Jimenez Waldo , Heunis Tiaan , Trost Matthias , Werling Dirk , Salguero Francisco J. , Gordon Stephen V. , Gutierrez Maximiliano G. 
Published: July 2020

AbstractTheMycobacterium tuberculosiscomplex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. WhileMycobacterium bovis(Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB,M. tuberculosis(Mtb) affects human populations and seldom causes disease in cattle. However, the host and pathogen determinants driving host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed both blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated cells (MNCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multi-nucleation. Importantly, we extend ourin vitrostudies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNCs. Our findings implicate MNC formation in the contrasting pathology between Mtb and Mbv for the bovine host, and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process.
Fine-scale Population Structure and Demographic History of Han Chinese Inferred from Haplotype Network of 111,000 Genomes
Authors: Lan Ao , Kang Kang , Tang Senwei , Wu Xiaoli , Wang Lizhong , Li Teng , Weng Haoyi , Deng Junjie ,   WeGene Research Team, Zheng Qiang , Yao Xiaotian , Chen Gang 
Published: July 2020

ABSTRACTHan Chinese is the most populated ethnic group across the globe with a comprehensive substructure that resembles its cultural diversification. Studies have constructed the genetic polymorphism spectrum of Han Chinese, whereas high-resolution investigations are still missing to unveil its fine-scale substructure and trace the genetic imprints for its demographic history. Here we construct a haplotype network consisted of 111,000 genome-wide genotyped Han Chinese individuals from direct-to-consumer genetic testing and over 1.3 billion identity-by-descent (IBD) links. We observed a clear separation of the northern and southern Han Chinese and captured 5 subclusters and 17 sub-subclusters in haplotype network hierarchical clustering, corresponding to geography (especially mountain ranges), immigration waves, and clans with cultural-linguistic segregation. We inferred differentiated split histories and founder effects for population clans Cantonese, Hakka, and Minnan-Chaoshanese in southern China, and also unveiled more recent demographic events within the past few centuries, such asZou XikouandChuang Guandong. The composition shifts of the native and current residents of four major metropolitans (Beijing, Shanghai, Guangzhou, and Shenzhen) imply a rapidly vanished genetic barrier between subpopulations. Our study yields a fine-scale population structure of Han Chinese and provides profound insights into the nation’s genetic and cultural-linguistic multiformity.
Amino acid substitutions associated with treatment failure of hepatitis C virus infection
Authors: Soria María Eugenia , García-Crespo Carlos , Martínez-Gónzalez Brenda , Vázquez-Sirvent Lucía , Lobo-Vega Rebeca , de Ávila Ana Isabel , Gallego Isabel , Chen Qian , García-Cehic Damir , Llorens-Revull Meritxell , Briones Carlos , Gómez Jordi , Ferrer-Orta Cristina , Verdaguer Nuria , Gregori Josep , Rodríguez-Frías Francisco , Buti María , Esteban Juan Ignacio , Domingo Esteban , Quer Josep , Perales Celia 
Published: July 2020

AbstractDespite the high virological response rates achieved with current directly-acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. Identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultra-deep sequencing (UDS) methods for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV from 220 patients who failed therapy, which are notbona fideresistance-associated substitutions (RAS). They were present frequently in basal and post-treatment virus of patients who failed therapy to different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Coherently, their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. Also, they have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value of treatment response are discussed.
Accelerated tissue repair through cell proliferative effect by a size controlled aqueous based Fullerene C60nanoformulation
Authors: Sinha Nabodita , Gahane Avinash Y. , Thakur Ashwani Kumar 
Published: July 2020

AbstractWe have developed Fullerene-C60nanoformulations containing discrete sized nanoparticles by dispersing concentration range of Fullerene. Small sized particles are cytotoxic while larger ones are cell proliferative. The cell proliferative property is used for tissue repair in cellular and animal wound models.
In-vitroevaluation ofPseudomonas fluorescensantibacterial activity againstListeriaspp. isolated from New Zealand horticultural environments
Authors: Mohan Vathsala , Fletcher Graham , Leroi Françoise 
Published: July 2020

AbstractBeneficial bacteria with antibacterial properties are an attractive alternative to chemical-based antibacterial or bactericidal agents. The aim of our study was to source such bacteria from horticultural produce and environments and to explore the mechanisms of their antimicrobial properties. Four strains ofPseudomonas fluorescenswere isolated that possessed antibacterial activity against the pathogenListeria monocytogenes.These strains (PFR46H06, PFR46H07, PFR46H08 and PFR46H09) were tested againstL. monocytogenes(n=31),L. seeligeri(n=1) andL. innocua(n=1) isolated from seafood and horticultural sources, and twoL. monocytogenesfrom clinical cases (Scott A and ATCC 49594, n=2). AllListeriastrains were inhibited by the three strains PFR46H07, PFR46H08 and PFR46H09 with average zones of inhibition of 14.8, 15.1 and 18.2 mm, respectively, with PFR46H09 having significantly more inhibition than the other two (p<0.05). PFR46H06 showed minimal inhibition towards theL. seeligeriandL. innocuaisolates and no inhibition towards most of theL. monocytogenesisolates. In order to investigate the functional protein differences between these strains, all four strains were subjected to whole cell lysate proteomics; data are available via ProteomeXchange with identifier PXD019965. We found significant differences in the peptide profiles and protein summaries between these isolates. The total number of proteins identified was 1781 in PFR46H06, 2030 in PFR46H07, 2228 in PFR46H08 and 1994 in PFR46H09. We paid special attention to secretion system proteins as these play a main role in the defense mechanisms of bacteria, particularly those of the type VI secretion system (T6SS) and found that they varied significantly (p<0.001) among the four isolates. PFR46H06 and PFR46H07 possessed the fewest secretion system structural proteins (12 and 11 respectively) while PFR46H08 and PFR46H09 each had 18. PFR46H09, which showed the greatest antimicrobial effect, had nine T6SS proteins compared to just four in the other three strains.