bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical transitions in malaria transmission models are consistently generated by superinfection
Authors: Alonso David , Dobson Andy , Pascual Mercedes 
Published: June 2018

AbstractThe history of infectious disease modelling essentially begins with the papers by Ross on malaria [1–5]. These models assume that the dynamics of malaria can most simply be characterized by two equations that describe the prevalence of malaria in the human and mosquito hosts. This structure has formed the central core of models for malaria and most other vector-borne diseases for the last century with occasional additions acknowledging important aetiological details. We partially add to this tradition by describing a malaria model that provides for vital dynamics in the vector and the possibility of super-infection in the human host; reinfection of asymptomatic hosts before they have cleared a prior infection. These key features of malaria aetiology create the potential for break points in the prevalence of infected hosts, sudden transitions that seem to characterize malaria’s response to control in different locations. We show that this potential for critical transitions is a general and underappreciated feature of any model for vector borne diseases with incomplete immunity and asymptomatic patients, including the canonical Ross-McDonald model. Ignoring these details of the host’s immune response to infection can potentially lead to serious misunderstanding in the interpretation of malaria distribution patterns and the design of control schemes for other vector-borne diseases.
Meta-analysis of 1,200 transcriptomic profiles identifies a prognostic model for pancreatic ductal adenocarcinoma
Authors: Sandhu Vandana , Labori Knut Jorgen , Borgida Ayelet , Lungu Ilinca , Bartlett John , Hafezi-Bakhtiari Sara , Denroche Rob , Jang Gun Ho , Pasternack Danielle , Mbaabali Faridah , Watson Matthew , Wilson Julie , Kure Elin H. , Gallinger Steven , Haibe-Kains Benjamin 
Published: June 2018

ABSTRACTBackgroundWith a dismal 8% median 5-year overall survival (OS), pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Only 10-20% of patients are eligible for surgery, and over 50% of these will die within a year of surgery. Identify molecular predictors of early death would enable the selection of PDAC patients at high risk.MethodsWe developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors where gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework based on the binary gene pair method to create gene expression barcodes robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic datasets to date, we show that PCOSP is a robust single-sample predictor of early death (≤1 yr) after surgery in a subset of 823 samples with available transcriptomics and survival data.ResultsThe PCOSP model was strongly and significantly prognostic with a meta-estimate of the area under the receiver operating curve (AUROC) of 0.70 (P=1.9e-18) and hazard ratio (HR) of 1.95(1.6-2.3) (P=2.6e-16) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathological parameters and molecular subtypes. Over-representation analysis of the PCOSP 2619 gene-pairs (1070 unique genes) unveiled pathways associated with Hedgehog signalling, epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) signalling.ConclusionPCOSP could improve treatment decision by identifying patients who will not benefit from standard surgery/chemotherapy and may benefit from alternate approaches.AbbreviationsAUROCArea under the receiver operating curveGOGene annotationOSOverall survivalPCOSPPancreatic cancer overall survival predictorPDACPancreatic ductal adenocarcinomaTSPTop scoring pairs.
Gene-regulatory independent functions for insect DNA methylation
Authors: Bewick Adam J. , Sanchez Zachary , Mckinney Elizabeth C. , Moore Allen J. , Moore Patricia J. , Schmitz Robert J. 
Published: June 2018

AbstractThe function of cytosine (DNA) methylation in insects remains unknown. Here we provide evidence for the functional role of the maintenance DNA methyltransferase 1 (Dnmt1) in an insect using experimental manipulation. Through RNA interference (RNAi) we successfully post-transcriptionally knocked downDnmt1in ovarian tissue of the hemipteranOncopeltus fasciatus(the large milkweed bug). Individuals depleted forDnmt1, and subsequently DNA methylation, failed to reproduce. Eggs were inviable and declined in number, and nuclei structure of follicular epithelium was aberrant. Depletion of DNA methylation did not result in changes in gene or transposable element expression revealing an important function of DNA methylation seemingly not contingent on gene expression. Our work provides direct experimental evidence for a functional role ofDnmt1and DNA methylation independent of gene expression in insects.
CellSpecks: A Software for Automated Detection and Analysis of Calcium Channels in Live Cells
Authors: Shah S I , Smith M , Swaminathan D , Parker I , Ullah G , Demuro A 
Published: June 2018

ABSTRACTTo couple the fidelity of patch-clamp recording with a more high-throughput screening capability, we pioneered a novel approach to single channel recording that we named “optical patch clamp”. By using highly-sensitive fluorescent Ca2+ indicator dyes in conjunction with total internal fluorescence microscopy techniques, we monitor Ca2+ flux through individual Ca2+-permeable channels. This approach provides information about channel gating analogous to patch-clamp recording at time resolution of ~ 2 ms, with the additional advantage of being massively parallel, providing simultaneous and independent recording from thousands of channels in native environment. However, manual analysis of the data generated by this technique presents severe challenges as a video recording can include many thousands of frames. To overcome this bottleneck, we developed an image processing and analysis framework called CellSpecks, capable of detecting and fully analyzing the kinetics of ion channels within a video sequence. By using a randomly generated synthetic data, we tested the ability of CellSpecks to rapidly and efficiently detect and analyze the activity of thousands of ion channels, including openings for a few milliseconds. Here, we report the use of CellSpecks for the analysis of experimental data acquired by imaging muscle nicotinic acetylcholine receptors and the Alzheimer’s disease-associated amyloid beta pores with multiconductance levels in the plasma membrane of Xenopus laevis oocytes. We show that CellSpecks can accurately and efficiently generate location maps, create raw and processed fluorescence time-traces, histograms of mean open times, mean close times, open probabilities, durations, and maximum amplitudes, and a ‘channel chip’ showing the activity of all channels as a function of time. Although we specifically illustrate the application of CellSpecks for analyzing data from Ca2+ channels, it can be easily customized to analyze other spatially and temporally localized signals.
Canonical Wnt signaling regulates patterning, differentiation and nucleogenesis in mouse hypothalamus and prethalamus
Authors: Newman Elizabeth A. , Wu Dan , Taketo Makoto Mark , Zhang Jiangyang , Blackshaw Seth 
Published: June 2018

AbstractThe hypothalamus is a small, but anatomically and functionally complex, region of the brain whose development is poorly understood. In this study, we have explored its development by studying the canonical Wntsignalling pathway, generating gain and loss of function mutations of betacaten in(Ctnnb1) in both hypothalamic and prethalamic neuroepithelium. Deletion ofCtnnb1resulted in an anteriorized and hypoplastic hypothalamus. Posterior structures were lost or reduced, and anterior structures were expanded. In contrast, over expression of a constitutively active mutant form ofCtnnb1resulted in severe hyperplasia of prethalamus and hypothalamus, and expanded expression of a subset of posterior and premamillary hypothalamic markers. Moderate defects in differentiation ofArx-positive GABAergic neural precursors were observed in both prethalamus and hypothalamus ofCtnnb1loss of function mutants, while in gain of function mutants, their differentiation was completely suppressed, although markers of prethalamic progenitors were preserved. Multiple other region-specific markers, including several specific posterior hypothalamic structures, were also suppressed inCtnnb1gain of function mutations. Severe, region-specific defects in hypothalamic nucleogenesis were also observed in both gain and loss of function mutations ofCtnnb1. Finally, both gain and loss of function ofCtnnb1also produced severe, cell nonautonomous disruptions of pituitary development. These findings demonstrate acentral and multifaceted role for canonical Wnt signalling in regulating growth, patterning, differentiation and nucleogenesis in multiple diencephalic regions.HighlightsCanonical Wnt signalling regulates anteroposterior patterning in the hypothalamus.Canonical Wnt signalling regulates differentiation of GABAergic neurons in both prethalamus and hypothalamus.Canonical Wnt signalling regulates differentiation and nucleogenesis of multiple hypothalamic neuronal subtypes.Canonical Wnt signalling in hypothalamic neuroepithelium regulates pituitary morphogenesis and differentiation.
Temporal ordering of input modulates connectivity formation in a developmental neuronal network model of the cortex
Authors: Hartley Caroline , Farmer Simon , Berthouze Luc 
Published: June 2018

AbstractPreterm infant brain activity is discontinuous; bursts of activity recorded using EEG (electroencephalography), thought to be driven by subcortical regions, display scale free properties and exhibit a complex temporal ordering known as long-range temporal correlations (LRTCs). During brain development, activity-dependent mechanisms are essential for synaptic connectivity formation, and abolishing burst activity in animal models leads to weak disorganised synaptic connectivity. Moreover, synaptic pruning shares similar mechanisms to spike-timing dependent plasticity (STDP), suggesting that the timing of activity may play a critical role in connectivity formation. We investigated, in a computational model of leaky integrate-and-fire neurones, whether the temporal ordering of burst activity within an external driving input could modulate connectivity formation in the network. Connectivity evolved across the course of simulations using an approach analogous to STDP, from networks with initial random connectivity. Small-world connectivity and hub neurones emerged in the network structure - characteristic properties of mature brain networks. Notably, driving the network with an external input which exhibited LRTCs in the temporal ordering of burst activity facilitated the emergence of these network properties, increasing the speed with which they emerged compared with when the network was driven by the same input with the bursts randomly ordered in time. Moreover, the emergence of small-world properties was dependent on the strength of the LRTCs. These results suggest that the temporal ordering of burst activity could play an important role in synaptic connectivity formation and the emergence of small-world topology in the developing brain.
Experimental infection characteristics ofBordetellapertussis via aerosol challenge on rhesus macaques
Authors: Mou Dachao , Luo Peng , Liang Jiangli , Ji Qiuyan , Wang Lichan , Gao Na , Gu Qin , Wei Chen , Ma Yan , Li Jingyan , Liu Shuyuan , Shi Li , Sun Mingbo 
Published: June 2018

AbstractThe effect of aerosol challenge of rhesus macaques withBordetella pertussisand the feasibility of using rhesus monkeys as an animal model for pertussis infection were evaluated in this study. Four 1-year old rhesus macaques were aerosol challenged withB. pertussisat the concentration of 105CFU/mL for 30 min (group 1) or 60 min (group 2). Rectal temperature was found slightly increased at days 3 and 5 and returned to baseline levels at day 21 after challenge. White blood cell counts peaked at day 7, with a 4.7~6.1-fold increase and returned to baseline levels at day 45. Bacteria colonization of nasopharyngeal swabs was observed, and the number of colonies was gradually increased and peaked at day 14, reaching 5.4-8.1 × 106/mL. The seroconversion rate of anti-pertussis toxin (PT), pertactin (PRN), and filamentous hemagglutinin(FHA) antibodies was 100%, with an increase in geometric mean titers after challenge. Analysis of cytokines revealed that the levels of cytokines including IL-2, IL-6, IL-8, IL-10, IL-17A, IL-13, IL-12, and IL-18 were significantly increased at days 5 to 14 in group 2. These results demonstrate that the characteristic of pertussis infection in infant rhesus macaque was similar as in human beings, which provide a clue to using infant rhesus macaque as a candidate model for pertussis infection in the future studies
Two point mutations in the Hantaan virus glycoproteins afford the generation of a highly infectious recombinant vesicular stomatitis virus vector
Authors: Slough Megan M. , Chandran Kartik , Jangra Rohit K. 
Published: June 2018

AbstractRodent-to-human transmission of hantaviruses is associated with severe disease. Currently, no FDA-approved, specific antivirals or vaccines are available, and the requirement for high biocontainment (BSL3) laboratories limits hantavirus research. To study hantavirus entry in a BSL-2 laboratory, we set out to generate replication-competent, recombinant vesicular stomatitis viruses (rVSVs) bearing the Gn/Gc entry glycoproteins. As previously reported, rVSVs bearing New World hantavirus Gn/Gc were readily rescued from cDNAs, but their counterparts bearing Gn/Gc from the Old World hantavirus, Hantaan virus (HTNV), were refractory to rescue and only grew to low titers. However, serial passage of the rescued rVSV-HTNV Gn/Gc virus markedly increased its infectivity and capacity for cell-to-cell spread. This gain in viral fitness was associated with the acquisition of two point mutations; I532K in the cytoplasmic tail of Gn, and S1094L in the membrane-proximal stem of Gc. Follow-up experiments with rVSVs and single-cycle VSV pseudotypes confirmed these results. Mechanistic studies revealed that both mutations were determinative and contributed to viral infectivity in a synergistic manner. Our findings indicate that the primary mode of action of these mutations is to relocalize HTNV Gn/Gc from the Golgi complex to the cell surface, thereby affording significantly enhanced Gn/Gc incorporation into budding VSV particles. Our results suggest that enhancements in cell-surface expression of hantaviral glycoprotein(s) through incorporation of cognate mutations could afford the generation of rVSVs that are otherwise challenging to rescue. The robust replication-competent rVSV-HTNV Gn/Gc reported herein may also have utility as a vaccine.ImportanceHuman hantavirus infections cause pulmonary syndrome in the Americas and hemorrhagic fever with renal syndrome (HFRS) in Eurasia. No FDA-approved vaccines and therapeutics exist for these deadly viruses, and their development is limited by the requirement for high biocontainment. In this study, we identified and characterized key amino acid changes in the surface glycoproteins of HFRS-causing Hantaan virus that enhance their incorporation into recombinant vesicular stomatitis virus (rVSV) particles. The replication-competent rVSV genetically encoding Hantaan virus glycoproteins described in this work provides a powerful and facile system to study hantavirus entry under lower biocontainment and may have utility as a hantavirus vaccine.
Single-trial characterization of neural rhythms: potential and challenges
Authors: Kosciessa Julian Q. , Grandy Thomas H. , Garrett Douglas D. , Werkle-Bergner Markus 
Published: June 2018

AbstractThe average power of rhythmic neural responses as captured by MEG/EEG/LFP recordings is a prevalent index of human brain function. Increasing evidence questions the utility of trial-/group averaged power estimates, as seemingly sustained activity patterns may be brought about by time-varying transient signals in each single trial. Hence, it is crucial to accurately describe the duration and power of rhythmic and arrhythmic neural responses on the single trial-level. However, it is less clear how well this can be achieved in empirical MEG/EEG/LFP recordings. Here, we extend an existing rhythm detection algorithm (extended Better OSCillation detection: “eBOSC”; cf. Whitten et al., 2011) to systematically investigate boundary conditions for estimating neural rhythms at the single-trial level. Using simulations as well as resting and task-based EEG recordings from a micro-longitudinal assessment, we show that alpha rhythms can be successfully captured in single trials with high specificity, but that the quality of single-trial estimates varies greatly between subjects. Importantly, our analyses suggest that rhythmic estimates are reliable within-subject markers, but may not be consistently valid descriptors of the individual rhythmic process. Finally, we highlight the utility and potential of rhythm detection with multiple proof-of-concept examples, and discuss various implications for single-trial analyses of neural rhythms in electrophysiological recordings.HighlightsTraditional narrow-band rhythm metrics conflate the power and duration of rhythmic and arrhythmic periods.We extend a state-of-the-art rhythm detection method (eBOSC) to derive rhythmic episodes in single trials that can disambiguate rhythmic and arrhythmic periods.Simulations indicate that this can be done with high specificity given sufficient rhythmic power, but with strongly impaired sensitivity when rhythmic power is low.Empirically, surface EEG recordings exhibit stable inter-individual differences in α-rhythmicity in ranges where simulations suggest a gradual bias, leading to high collinearity between narrow-band and rhythm-specific estimates.Beyond these limitations, we highlight multiple empirical proof-of-concept benefits of characterizing rhythmic episodes in single trials.
Efficient whole genome haplotyping and high-throughput single molecule phasing with barcode-linked reads
Authors: Redin David , Frick Tobias , Aghelpasand Hooman , Theland Jennifer , Käller Max , Borgström Erik , Olsen Remi-Andre , Ahmadian Afshin 
Published: June 2018

ABSTRACTThe future of human genomics is one that seeks to resolve the entirety of genetic variation through sequencing. The prospect of utilizing genomics for medical purposes require cost-efficient and accurate base calling, long-range haplotyping capability, and reliable calling of structural variants. Short read sequencing has lead the development towards such a future but has struggled to meet the latter two of these needs1. To address this limitation, we developed a technology that preserves the molecular origin of short sequencing reads, with an insignificant increase to sequencing costs. We demonstrate a novel library preparation method which enables whole genome haplotyping, long-range phasing of single DNA molecules, and de novo genome assembly through barcode-linked reads (BLR). Millions of random barcodes are used to reconstruct megabase-scale phase blocks and call structural variants. We also highlight the versatility of our technology by generating libraries from different organisms using only picograms to nanograms of input material.
Architectural traits constrain the evolution of unisexual flowers and sexual segregation within inflorescences: an interspecific approach
Authors: Torices Rubén , Afonso Ana , Anderberg Arne A. , Gómez José M. , Méndez Marcos 
Published: June 2018

ABSTRACTMale and female unisexual flowers have repeatedly evolved from the ancestral bisexual flowers in different lineages of flowering plants. This sex specialization in different flowers often occurs within inflorescences. We hypothesize that inflorescence architecture may impose a constraint on resource availability for late flowers, potentially leading to different optima in floral sex allocation and unisexuality. Under this hypothesis we expect that inflorescence traits increasing the difference in resource availability between early and late flowers would be phylogenetically correlated with a higher level of sexual specialization. To test this hypothesis, we performed a comparative analysis of inflorescence traits (inflorescence size, number of flowers and flower density) in the sunflower family, which displays an extraordinary variation in floral sexual specialization at the inflorescence level, i.e. hermaphroditic, gynomonoecious and monoecious species. We found that species with a complete sex separation in unisexual flowers (monoecy) had significantly denser inflorescences. Furthermore, those species arranging their flowers in denser inflorescences also showed greater differences in the size of early and late fruits, a proxy of resource variation between flowers. Our findings support the idea that floral sexual specialization and consequently sexual segregation may be the consequence of different floral sex allocation optima driven by the sequential development of flowers that results in a persistent resource decline from earlier to later flowers.
In-depth investigation of the species problem and taxonomic status of marbled crayfish, the first asexual decapod crustacean
Authors: Vogt Günter , Dorn Nathan J. , Pfeiffer Michael , Lukhaup Chris , Williams Bronwyn W. , Schulz Ralf , Schrimpf Anne 
Published: June 2018

ABSTRACTThe marbled crayfish is the only obligately parthenogenetic decapod crustacean and a novel research model and invasive animal on three continents. It is regarded either as a parthenogenetic form of slough crayfishProcambarus fallaxor as a separate species namedProcambarus virginalis.In order to investigate the species question of this unusual crayfish in detail we have identified the similarities and differences in morphology, life history, genetics, behaviour, ecology and biogeography between marbled crayfish and its most likely parent speciesP. fallax.We have investigated specimens from natural habitats, laboratory colonies and museum collections and performed a meta-analysis of our data and published data. OurCOIbased molecular tree with 27 Cambaridae confirms closest relationship of marbled crayfish withP. fallax.Marbled crayfish andP. fallaxare similar with respect to morphological characters, coloration and body proportions, but differ considerably with respect to body size, fertility and longevity. The mitochondrial genes of both crayfish are similar, but ploidy level and haploid genome size are markedly different. Both crayfish are eurytopic and have two major annual recruitment periods, but marbled crayfish show different population structure and higher invasiveness. Marbled crayfish occur in tropical to cold temperate habitats of the old world, butP. fallaxis confined to subtropical and warm-temperate habitats of the southeastern USA. Cross-breeding experiments with both crayfish revealed reproductive isolation. The application of the Evolutionary Genetic Species Concept for asexuals to all available data supports raising marbled crayfish from “forma” to species rank. A determination key is provided to discriminateProcambarus virginalis, the first asexual decapod species, from its parent speciesP. fallax.