bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unravelling the effect of a potentiating anti-Factor H antibody on atypical hemolytic uremic syndrome associated factor H variants
Authors: Dekkers Gillian , Brouwer Mieke , Jeremiasse Jorn , Kamp Angela , Biggs Robyn M. , van Mierlo Gerard , Lauder Scott , Katti Suresh , Kuijpers Taco W. , Rispens Theo , Jongerius Ilse 
Published: April 2020

AbstractThe complement system plays an important role in our innate immune system. Complement activation results in clearance of pathogens, immune complex and apoptotic cells. The host is protected from complement-mediated damage by several complement regulators. Factor H (FH) is the most important fluid-phase regulator of the alternative pathway of the complement system. Heterozygous mutations in FH are associated with complement-related diseases such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration.We recently described an agonistic anti-FH monoclonal antibody that can potentiate the regulatory function of FH. This antibody could serve as a potential new drug for aHUS patients and alternative to C5 blockade by Eculizumab. However, it is unclear whether this antibody can potentiate FH mutant variants in addition to wild type FH. Here, the functionality and potential of the agonistic antibody in the context of pathogenic aHUS-related FH mutant proteins was investigated. The binding affinity of recombinant WT FH, and the FH variants, W1183L, V1197A, R1210C, and G1194D to C3b was increased upon addition of the potentiating antibody and similarly, the decay accelerating activity of all mutants is increased. The potentiating anti-FH antibody is able to restore the surface regulatory function of most of the tested FH mutants to WT FH levels. In conclusion, our potentiating anti-FH is broadly active and able to enhance both WT FH function as well as most aHUS-associated FH variants tested in this study.
Phage and bacteria diversification through a prophage acquisition ratchet
Authors: Anthenelli Maxwell , Jasien Emily , Edwards Robert , Bailey Barbara , Felts Ben , Katira Parag , Nulton James , Salamon Peter , Rohwer Forest , Silveira Cynthia B. , Luque Antoni 
Published: April 2020

AbstractLysogeny is prevalent in the microbial-dense mammalian gut. This contrasts the classical view of lysogeny as a refuge used by phages under poor host growth conditions. Here we hypothesize that as carrying capacity increases, lysogens escape phage top-down control through superinfection exclusion, overcoming the canonical trade-off between competition and resistance. This hypothesis was tested by developing an ecological model that combined lytic and lysogenic communities and a diversification model that estimated the accumulation of prophages in bacterial genomes. The ecological model sampled phage-bacteria traits stochastically for communities ranging from 1 to 1000 phage-bacteria pairs, and it included a fraction of escaping lysogens proportional to the increase in carrying capacity. The diversification model introduced new prophages at each diversification step and estimated the distribution of prophages per bacteria using combinatorics. The ecological model recovered the range of abundances and sublinear relationship between phage and bacteria observed across eleven ecosystems. The diversification model predicted an increase in the number of prophages per genome as bacterial abundances increased, in agreement with the distribution of prophages on 833 genomes from marine and human-associated bacteria. The study of lysogeny presented here offers a framework to interpret viral and microbial abundances and reconciles the Kill-the-Winner and Piggyback-the-Winner paradigms in viral ecology.
BSAseq: an interactive and integrated web-based workflow for identification of causal mutations in bulked F2 populations
Authors: Wang Liya , Lu Zhenyuan , Regulski Michael , Jiao Yinping , Chen Junping , Ware Doreen , Xin Zhanguo 
Published: April 2020

AbstractSummaryWith the advance of next-generation sequencing (NGS) technologies and reductions in the costs of these techniques, bulked segregant analysis (BSA) has become not only a powerful tool for mapping quantitative trait loci (QTL) but also a useful way to identify causal gene mutations underlying phenotypes of interest. However, due to the presence of background mutations and errors in sequencing, genotyping, and reference assembly, it is often difficult to distinguish true causal mutations from background mutations. In this study, we developed the BSAseq workflow, which includes an automated bioinformatics analysis pipeline with a probabilistic model for estimating the segregation region and an interactive Shiny web application for visualizing the results. We deeply sequenced a male sterile parental line (ms8) to capture the majority of background mutations in our bulked F2 data. We applied the workflow to 11 bulked F2 populations and identified the true causal mutation in each population. The workflow is intuitive and straightforward, facilitating its adoption by users without bioinformatics analysis skills. We anticipate that BSAseq will be broadly applicable to the identification of causal mutations for many phenotypes of interest.AvailabilityBSAseq is freely available onhttps://www.sciapps.org/page/bsaContactliya.wang@cshl.edu,ware@cshl.edu,zhanguo.xin@ars.usda.gov
Mortality and coexistence time both cause changes in predator-prey co-evolutionary dynamics
Authors: Scheuerl Thomas , Kaitala Veijo 
Published: April 2020

AbstractAll organisms are sensitive to the abiotic environment, and in multispecies communities a deteriorating environment increasing mortality and limiting coexistence time can cause ecological changes. When interaction within the community is changed this can impact co-evolutionary processes. Here we use a mathematical model to predict ecological and evolutionary changes in a simple predator-prey community under different mortality rates and times of coexistence, both controlled by various transfer volume and transfer interval. In the simulated bacteria-ciliate system, we find species densities to be surprisingly robust under changed mortality rates and times both species coexist, resulting in stable densities. Confirming a theoretical prediction however, the evolution of anti-predator defence in the bacteria and evolution of predation efficiency in ciliates relax under high mortalities and limited times both partners interact. In contrast, evolutionary trajectories intensify when global mortalities are low, and the predator-prey community has more time for close interaction. These results provide testable hypotheses for future studies of predator-prey systems and we hope this work will help to bridge the gap in our knowledge how ecological and evolutionary process together shape composition of microbial communities.
Unique Evolution of Antiviral Tetherin in Bats
Authors: Hayward Joshua A. , Tachedjian Mary , Johnson Adam , Irving Aaron T. , Gordon Tamsin B. , Cui Jie , Nicolas Alexis , Smith Ina , Boyd Victoria , Marsh Glenn A. , Baker Michelle L. , Wang Lin-Fa , Tachedjian Gilda 
Published: April 2020

AbstractBats are recognised as important reservoirs of viruses deadly to other mammals, including humans. These infections are typically non-pathogenic in bats raising questions about host response differences that might exist between bats and other mammals. Tetherin is a restriction factor which inhibits the release of a diverse range of viruses from host cells, including retroviruses, coronaviruses, filoviruses, and paramyxoviruses, some of which are deadly to humans and transmitted by bats. Here we characterise the tetherin genes from 27 species of bats, revealing that they have evolved under strong selective pressure, and that fruit bats and vesper bats express unique structural variants of the tetherin protein. Tetherin was widely and variably expressed across fruit bat tissue-types and upregulated in spleen tissue when stimulated with Toll-like receptor agonists. The expression of two computationally predicted splice isoforms of fruit bat tetherin was verified. We identified an additional third unique splice isoform which includes a C-terminal region that is not homologous to known mammalian tetherin variants but was functionally capable of restricting the release of filoviral virus-like particles. We also report that vesper bats possess and express at least five tetherin genes, including structural variants, a greater number than any other mammal reported to date. These findings support the hypothesis of differential antiviral gene evolution in bats relative to other mammals.
Clonal thermal preferences affect the strength of the temperature-size rule
Authors: Stuczyńska Anna , Sobczyk Mateusz , Fiałkowska Edyta , Kocerba-Soroka Wioleta , Pajdak-Stós Agnieszka , Starzycka Joanna , Walczyńska Aleksandra 
Published: April 2020

AbstractGenetically similar organisms act as a powerful study system for the subtle differences in various aspects of life histories. The issue of trade-offs among traits is of special interest. We used six parthenogenetic rotifer clones previously exposed to different thermal laboratory conditions. Interclonal differences in female body size were examined in common garden conditions. We estimated the population growth rate and strength of the size-to-temperature response across four thermal regimes. We tested hypotheses on the existence of the relationships between (i) thermal acclimation and species body size, (ii) thermal specialization and fitness and (iii) thermal specialization and strength of the temperature-size rule. Positive verification of (i) would make it justifiable to refer the other investigated traits to thermal preference and, further, to thermal specialization. Addressing the issues (ii) and (iii) is our pioneering contribution to the question on the strength of size-to-temperature response as differing across life strategies. We hypothesized that this plastic response may be affected by the level of thermal specialization and that this pattern may be traded off with the temperature-dependent potential for population growth rate. Additionally, we investigated the differences in reproductive strategy (number of eggs laid by a female and female lifetime duration) in one temperature assumed optimal, which acts as an important supplement to the general clonal life strategy. We confirmed that the thermal acclimation of a clone is related to body size, with clones acclimated to higher temperatures being smaller. We also found that warm-acclimated clones have a narrower thermal range (= are more specialized), and that the temperature-size rule is stronger in rotifers acclimated to intermediate thermal conditions than in specialists. Our results contribute into the issue of trade-offs between generalist and specialist strategies, in the context of plastic body size respone to different temperatures.
Delay-dependent cholinergic modulation of visual short-term memory in rhesus macaques
Authors: Knakker Balázs , Oláh Vilmos , Trunk Attila , Lendvai Balázs , Lévay György , Hernádi István 
Published: April 2020

AbstractCholinergic neuromodulation is known to play a key role in visual working memory (VWM) – keeping relevant stimulus representations available for cognitive processes for short time periods up to a few minutes. Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N=6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimer’s medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.
Topographic Connectivity in a Duration Selective Cortico-Cerebellar Network
Authors: Protopapa Foteini , Hayashi Masamichi J. , Kanai Ryota , Bueti Domenica 
Published: April 2020

AbstractHow does the human brain represent millisecond unit of time? A recent neuroimaging study revealed the existence in the human premotor cortex of a topographic representation of time i.e., neuronal units selectively responsive to specific durations and topographically organized on the cortical surface. By using high resolution functional Magnetic Resonance Images here, we go futher this previous work, showing duration preferences across a wide network of cortical and subcortical brain areas: from cerebellum to primary visual, parietal, premotor and prefrontal cortices. Most importantly, we identify the functional connectivity structure between these different brain areas and their duration selective neural units. The results highlight the role of the cerebellum as the network hub and that of medial premotor cortex as the final stage of duration recognition. Interstingly, when a specific duration is presented, only the communication between the units selective to that duration become particularly “active”. These findings identify duration tuning and topographic connectivity as possible mechanisms underlying our capacity of telling time.
Neural harmonics of syntactic structure
Authors: Tavano Alessandro , Blohm Stefan , Knoop Christine A. , Muralikrishnan R , Fink Lauren , Scharinger Mathias , Wagner Valentin , Thiele Dominik , Ghitza Oded , Ding Nai , Menninghaus Winfried , Poeppel David 
Published: April 2020

AbstractCan neural rhythms reflect purely internal syntactic processes in multi-word constructions? To test this controversial conjecture - relevant to language in particular and cognition more broadly - we recorded electroencephalographic and behavioural data as participants listened to isochronously presented sentences of varying in syntactic complexity. Each trial comprised ten concatenated sentences and was either fully grammatical (regular) or rendered ungrammatical via randomly distributed word order violations. We found that attending the regular repetition of abstract syntactic categories (phrases and sentences) generates neural rhythms whose harmonics are mathematically independent of word rate. This permits to clearly separate endogenous syntactic rhythms from exogenous speech rhythms. We demonstrate that endogenous but not exogenous rhythms predict participants’ grammaticality judgements, and allow for the neural decoding of regular vs. irregular trials. Neural harmonic series constitute a new form of behaviourally relevant evidence for syntactic competence.
SweetOrigins: Extracting Evolutionary Information from Glycans
Authors: Bojar Daniel , Powers Rani K. , Camacho Diogo M. , Collins James J. 
Published: April 2020

AbstractGlycans, the most diverse biopolymer and crucial for many biological processes, are shaped by evolutionary pressures stemming in particular from host-pathogen interactions. While this positions glycans as being essential for understanding and targeting host-pathogen interactions, their considerable diversity and a lack of methods has hitherto stymied progress in leveraging their predictive potential. Here, we utilize a curated dataset of 12,674 glycans from 1,726 species to develop and apply machine learning methods to extract evolutionary information from glycans. Our deep learning-based language model SweetOrigins provides evolution-informed glycan representations that we utilize to discover and investigate motifs used for molecular mimicry-mediated immune evasion by commensals and pathogens. Novel glycan alignment methods enable us to identify and contextualize virulence-determining motifs in the capsular polysaccharide ofStaphylococcus aureusandAcinetobacter baumannii. Further, we show that glycan-based phylogenetic trees contain most of the information present in traditional 16S rRNA-based phylogenies and improve on the differentiation of genetically closely related but phenotypically divergent species, such asBacillus cereusandBacillus anthracis. Leveraging the evolutionary information inherent in glycans with machine learning methodology is poised to provide further – critically needed – insights into host-pathogen interactions, sequence-to-function relationships, and the major influence of glycans on phenotypic plasticity.
Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease
Authors: Fu Alexander Xi , Lui Kathy Nga-Chu , Tang Clara Sze-Man , Ng Ray Kit , Lai Frank Pui-Ling , Lau Sin-Ting , Li Zhixin , Gracia-Barcelo Maria-Mercè , Sham Pak-Chung , Tam Paul Kwong-Hang , Ngan Elly Sau-Wai , Yip Kevin Y. 
Published: April 2020

AbstractIt is widely recognized that the missing heritability of many human diseases is partially due to noncoding genetic variants, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals, and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multi-granular information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell-stage-specific regulatory roles three top novel regulatory elements on our list, respectively in theRET, RASGEF1AandPIK3C2Bloci. In thePIK3C2Bregulatory element, we further show that a noncoding variant found only in the affects the binding of the gliogenesis regulator NFIA, with a corresponding down-regulation of multiple genes in the same topologically associating domain.
Identification of Stem Cells from Large Cell Populations with Topological Scoring
Authors: Sardiu Mihaela E. , Andrew Box C. , Haug Jeff , Washburn Michael P. 
Published: April 2020

AbstractMachine learning and topological analysis methods are becoming increasingly used on various large-scale omics datasets. Modern high dimensional flow cytometry data sets share many features with other omics datasets like genomics and proteomics. For example, genomics or proteomics datasets can be sparse and have high dimensionality, and flow cytometry datasets can also share these features. This makes flow cytometry data potentially a suitable candidate for employing machine learning and topological scoring strategies, for example, to gain novel insights into patterns within the data. We have previously developed the Topological Score (TopS) and implemented it for the analysis of quantitative protein interaction network datasets. Here we show that the TopS approach for large scale data analysis is applicable to the analysis of a previously described flow cytometry sorted human hematopoietic stem cell dataset. We demonstrate that TopS is capable of effectively sorting this dataset into cell populations and identify rare cell populations. We demonstrate the utility of TopS when coupled with multiple approaches including topological data analysis, X-shift clustering, and t-Distributed Stochastic Neighbor Embedding (t-SNE). Our results suggest that TopS could be effectively used to analyze large scale flow cytometry datasets to find rare cell populations.
Identifying stem cell numbers and functional heterogeneities during post-embryonic organ growth
Authors: Danciu Diana-Patricia , Stolper Julian , Centanin Lázaro , Marciniak-Czochra Anna 
Published: April 2020

SummaryUncovering the number of stem cells necessary to grow an organ has been challenging in most vertebrate systems. Here, we have developed a mathematical model that we use to characterise stem cells in the fish gill, an organ that displays non-exhaustive growth. Our work employs a Markov model, first stochastically simulated via an adapted Gillespie algorithm, and further improved by using probability theory. The stochastic algorithm produces a simulated data set for comparison with experimental data by inspecting quantifiable properties, while the analytical approach skips the step ofin silicodata generation and goes directly to the quantification, being more abstract and very efficient. By applying the model to a large clonal experimental dataset, we report that a reduced number of stem cells are responsible for growing and maintaining the fish gill. The model also highlights a functional heterogeneity among the stem cells involved, where activation and quiescence phases determine their relative growth contribution. Overall, our work presents an easy-to-apply algorithm to infer the number of stem cells functionally required in a life-long growing system.
Climate change and green sea turtle sex ratio – Preventing possible extinction
Authors: Blechschmidt Jana , Wittmann Meike J. , Blüml Chantal 
Published: April 2020

AbstractClimate change poses a threat to species with temperature-dependent sex determination. A recent study on green sea turtles (Chelonia mydas)at the northern Great Barrier Reef (GBR) showed a highly female-skewed sex ratio with almost all juvenile turtles being female. This shortage of males might eventually cause population extinction, unless rapid evolutionary rescue, migration or conservation efforts ensure a sufficient number of males. We built a stochastic individual-based model inspired byC. mydas, but potentially transferrable to other species with TSD. Nest depth, level of shade, and pivotal temperature were evolvable traits. Additionally, we considered the effect of crossbreeding between the northern and southern GBR, nest-site philopatry, and conservation efforts. Among the evolvable traits, nest depth was the most likely to rescue the population in the face of climate change, but even here the more extreme climate-change scenario led to extinction. Surprisingly, nest-site philopatry elevated extinction rates. Conservation efforts to artificially increase nest depth promoted population survival and did not preclude trait evolution. Although extra information is needed to make reliable predictions for the fate of green sea turtles, our results illustrate how evolution can shape the fate of long lived, vulnerable species in the face of climate change.Graphical Abstract