bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonreimbursed Costs Incurred by Living Kidney Donors: A Case Study From Ontario, Canada
Authors: Barnieh Lianne , Klarenbach Scott , Arnold Jennifer , Cuerden Meaghan , Knoll Greg , Lok Charmaine , Sontrop Jessica M. , Miller Matthew , Ramesh Prasad G.V. , Przech Sebastian , Garg Amit X.
Published: March 2019

Background.

Living donors may incur out-of-pocket costs during the donation process. While many jurisdictions have programs to reimburse living kidney donors for expenses, few programs have been evaluated.

Methods.

The Program for Reimbursing Expenses of Living Organ Donors was launched in the province of Ontario, Canada in 2008 and reimburses travel, parking, accommodation, meals, and loss of income; each category has a limit and the maximum total reimbursement is $5500 CAD. We conducted a case study to compare donors’ incurred costs (out-of-pocket and lost income) with amounts reimbursed by Program for Reimbursing Expenses of Living Organ Donors. Donors with complete or partial cost data from a large prospective cohort study were linked to Ontario’s reimbursement program to determine the gap between incurred and reimbursed costs (n = 159).

Results.

The mean gap between costs incurred and costs reimbursed to the donors was $1313 CAD for out-of-pocket costs and $1802 CAD for lost income, representing a mean reimbursement gap of $3115 CAD. Nondirected donors had the highest mean loss for out-of-pocket costs ($2691 CAD) and kidney paired donors had the highest mean loss for lost income ($4084 CAD). There were no significant differences in the mean gap across exploratory subgroups.

Conclusions.

Reimbursement programs minimize some of the financial loss for living kidney donors. Opportunities remain to remove the financial burden of living kidney donors.
Long-term Assessment of NSAID Prescriptions and Potential Nephrotoxicity Risk in Adult Kidney Transplant Recipients
Authors: Chiasson Jordan M. , Fominaya Cory E. , Gebregziabher Mulugeta , Taber David J.
Published: March 2019

Background.

Nonsteroidal anti-inflammatory drug (NSAID) use is recommended to be avoided in kidney transplantation, with a paucity of studies assessing their safety within this population. This study aims to use a large cohort of Veterans Affairs (VA) kidney transplantation recipients to assess the risk of acute kidney injury (AKI) with NSAID use.

Methods.

This is a 10-year longitudinal cohort study of adult kidney transplant recipients retrospectively followed in the VA system from 2001 to 2010 that assessed for risk of AKI with NSAID prescriptions. NSAID prescriptions, patient characteristics, and estimated glomerular filtration rates were abstracted from the VA comprehensive electronic health record. NSAID exposure was assessed by duration, dosage, and type. AKI events were defined by ≥50% decrease in estimated glomerular filtration rate. Risk was estimated using longitudinal multivariable generalized logistic regression model.

Results.

About 5100 patients were included with a total of 29 980 years of follow-up; 671 NSAID prescriptions in 273 (5.4%) patients (2.24 per 100 patient-y) with 472 (70%) high dose were identified. High-dose NSAID prescriptions were associated with 2.83 (95% confidence interval [CI], 1.55-5.19; P < 0.001) higher odds of AKI events within a given year; low dose was not associated with AKI (odds ratio, 1.93; 95 % CI, 0.95-6.02; P = 0.256). One 7-day NSAID course was associated with 5% higher odds of increasing AKI events, whereas chronic use (≥180 d) was associated with 3.25 (95% CI, 1.78-5.97; P < 0.001) higher odds of AKI.

Conclusions.

Prescriptions for NSAIDs were uncommon in this cohort but were associated with a significant increase in the risk of AKI, which was impacted by higher NSAID dose and longer NSAID durations.
Vascular disease in the lower limb in type 1 diabetes
Authors: Edmonds Michael
Published: March 2019

This review considers peripheral arterial disease (PAD) in the diabetic ischaemic lower limb including both macrovascular and microvascular aspects. The presentation of PAD is probably not significantly different in type 1 compared with type 2 diabetes. PAD in diabetic patients is diffuse and located distally being most severe in the crural and also the foot arteries. It is associated with arterial calcification and occlusion of the arteries rather than stenosis. Compared with the nondiabetic patient, PAD develops at a younger age, and women are equally affected as men. It is not known whether the presentation of ischaemic lower limb disease in diabetes can be explained by one disease, namely, atherosclerosis, which has particular features peculiar to diabetes such as distal arterial involvement, or by the occurrence of two separate diseases: first, classical atherosclerosis and, second, a diabetic macroangiopathy, a term for nonatherosclerotic arterial disease in diabetes that is characterized by medial arterial calcification. Furthermore, there is controversy with regard to the significance of structural changes in the microcirculation of the diabetic foot.
Urban geography and scaling of contemporary Indian cities
Authors: Sahasranaman Anand , Bettencourt Luís M. A.
Published: March 2019

This paper attempts to create a first comprehensive analysis of the integrated characteristics of contemporary Indian cities, using scaling and geographical analysis over a set of diverse indicators. We use data of
urban agglomerations
in India from the Census 2011 and from a few other sources to characterize patterns of urban population density, infrastructure, urban services, crime and technological innovation. Many of the results are in line with expectations from urban theory and with the behaviour of analogous quantities in other urban systems in both high and middle-income nations. India is a continental scale, fast developing urban system, and consequently there are also a number of interesting exceptions and surprises related to both particular quantities and strong regional patterns of variation. Specifically, these relate to the potential salience of gender and caste in driving sub-linear scaling of crime and to the geography of technological innovation. We characterize these patterns in detail for crime and invention, and connect them to the existing literature on their determinants in a specifically Indian context. The paucity of data at the urban level and the absence of official definitions for functional cities in India create a number of limitations and caveats to any present analysis. We discuss these shortcomings and spell out the challenge for a systematic statistical data collection relevant to cities and urban development in India.
Partitioning a reaction–diffusion ecological network for dynamic stability
Authors: Kumar Dinesh , Gupta Jatin , Raha Soumyendu
Published: March 2019

The loss of dispersal connections between habitat patches may destabilize populations in a patched ecological network. This work studies the stability of populations when one or more communication links is removed. An example is finding the alignment of a highway through a patched forest containing a network of metapopulations in the patches. This problem is modelled as that of finding a stable cut of the graph induced by the metapopulations network, where nodes represent the habitat patches and the weighted edges model the dispersal between habitat patches. A reaction–diffusion system on the graph models the dynamics of the predator–prey system over the patched ecological network. The graph Laplacian's Fiedler value, which indicates the well-connectedness of the graph, is shown to affect the stability of the metapopulations. We show that, when the Fiedler value is sufficiently large, the removal of edges without destabilizing the dynamics of the network is possible. We give an exhaustive graph partitioning procedure, which is suitable for smaller networks and uses the criterion for both the local and global stability of populations in partitioned networks. A heuristic graph bisection algorithm that preserves the preassigned lower bound for the Fiedler value is proposed for larger networks and is illustrated with examples.
Geometry of the Kahan discretizations of planar quadratic Hamiltonian systems
Authors: Petrera Matteo , Smirin Jennifer , Suris Yuri B.
Published: March 2019

Kahan discretization is applicable to any quadratic vector field and produces a birational map which approximates the shift along the phase flow. For a planar quadratic canonical Hamiltonian vector field, this map is known to be integrable and to preserve a pencil of cubic curves. Generically, the nine base points of this pencil include three points at infinity (corresponding to the asymptotic directions of cubic curves) and six finite points lying on a conic. We show that the Kahan discretization map can be represented in six different ways as a composition of two Manin involutions, corresponding to an infinite base point and to a finite base point. As a consequence, the finite base points can be ordered so that the resulting hexagon has three pairs of parallel sides which pass through the three base points at infinity. Moreover, this geometric condition on the base points turns out to be characteristic: if it is satisfied, then the cubic curves of the corresponding pencil are invariant under the Kahan discretization of a planar quadratic canonical Hamiltonian vector field.
Investigations of ferroelectric polycrystalline bulks and thick films using piezoresponse force microscopy
Authors: Uršič Hana , Prah Uroš
Published: March 2019

In recent years, ferroelectric/piezoelectric polycrystalline bulks and thick films have been extensively studied for different applications, such as sensors, actuators, transducers and caloric devices. In the majority of these applications, the electric field is applied to the working element in order to induce an electromechanical response, which is a complex phenomenon with several origins. Among them is the field-induced movement of domain walls, which is nowadays extensively studied using piezoresponse force microscopy (PFM), a technique derived from atomic force microscopy. PFM is based on the detection of the local converse piezoelectric effect in the sample; it is one of the most frequently applied methods for the characterization of the ferroelectric domain structure due to the simplicity of the sample preparation, its non-destructive nature and its relatively high imaging resolution. In this review, we focus on the PFM analysis of ferroelectric bulk ceramics and thick films. The core of the paper is divided into four sections: (i) introduction; (ii) the preparation of the samples prior to the PFM investigation; (iii) this is followed by reviews of the domain structures in polycrystalline bulks; and (iv) thick films.
Fighting and mating success in giant Australian cuttlefish is influenced by behavioural lateralization
Authors: Schnell Alexandra K. , Jozet-Alves Christelle , Hall Karina C. , Radday Léa , Hanlon Roger T.
Published: March 2019

Behavioural lateralization is widespread. Yet, a fundamental question remains, how can lateralization be evolutionary stable when individuals lateralized in one direction often significantly outnumber individuals lateralized in the opposite direction? A recently developed game theory model predicts that fitness consequences which occur during intraspecific interactions may be driving population-level lateralization as an evolutionary stable strategy. This model predicts that: (i) minority-type individuals exist because they are more likely to adopt unpredictable fighting behaviours during competitive interactions (e.g. fighting); and (ii) majority-type individuals exist because there is a fitness advantage in having their biases synchronized with other conspecifics during interactions that require coordination (e.g. mating). We tested these predictions by investigating biases in giant Australian cuttlefish during fighting and mating interactions. During fighting, most male cuttlefish favoured the left eye and these males showed higher contest escalation; but minority-type individuals with a right-eye bias achieved higher fighting success. During mating interactions, most male cuttlefish favoured the left eye to inspect females. Furthermore, most male cuttlefish approached the female's right side during a mating attempt and these males achieved higher mating success. Our data support the hypothesis that population-level biases are an evolutionary consequence of the fitness advantages involved in intraspecific interactions.
When one phenotype is not enough: divergent evolutionary trajectories govern venom variation in a widespread rattlesnake species
Authors: Zancolli Giulia , Calvete Juan J. , Cardwell Michael D. , Greene Harry W. , Hayes William K. , Hegarty Matthew J. , Herrmann Hans-Werner , Holycross Andrew T. , Lannutti Dominic I. , Mulley John F. , Sanz Libia , Travis Zachary D. , Whorley Joshua R. , Wüster Catharine E. , Wüster Wolfgang
Published: March 2019

Understanding the origin and maintenance of phenotypic variation, particularly across a continuous spatial distribution, represents a key challenge in evolutionary biology. For this, animal venoms represent ideal study systems: they are complex, variable, yet easily quantifiable molecular phenotypes with a clear function. Rattlesnakes display tremendous variation in their venom composition, mostly through strongly dichotomous venom strategies, which may even coexist within a single species. Here, through dense, widespread population-level sampling of the Mojave rattlesnake,Crotalus scutulatus, we show that genomic structural variation at multiple loci underlies extreme geographical variation in venom composition, which is maintained despite extensive gene flow. Unexpectedly, neither diet composition nor neutral population structure explain venom variation. Instead, venom divergence is strongly correlated with environmental conditions. Individual toxin genes correlate with distinct environmental factors, suggesting that different selective pressures can act on individual loci independently of their co-expression patterns or genomic proximity. Our results challenge common assumptions about diet composition as the key selective driver of snake venom evolution and emphasize how the interplay between genomic architecture and local-scale spatial heterogeneity in selective pressures may facilitate the retention of adaptive functional polymorphisms across a continuous space.
Rainy springs linked to poor nestling growth in a declining avian aerial insectivore (
Tachycineta bicolor
)
Authors: Cox Amelia R. , Robertson Raleigh J. , Lendvai Ádám Z. , Everitt Kennedy , Bonier Frances
Published: March 2019

As species shift their ranges and phenology to cope with climate change, many are left without a ready supply of their preferred food source during critical life stages. Food shortages are often assumed to be driven by reduced total food abundance, but here we propose that climate change may cause short-term food shortages for foraging specialists without affecting overall food availability. We frame this hypothesis around the special case of birds that forage on flying insects for whom effects mediated by their shared food resource have been proposed to cause avian aerial insectivores' decline worldwide. Flying insects are inactive during cold, wet or windy conditions, effectively reducing food availability to zero even if insect abundance remains otherwise unchanged. Using long-term monitoring data from a declining population of tree swallows (
Tachycineta bicolor
), we show that nestlings’ body mass declined substantially from 1977 to 2017. In 2017, nestlings had lower body mass if it rained during the preceding 3 days, though females increased provisioning rates, potentially in an attempt to compensate. Adult body mass, particularly that of the males, has also declined over the long-term study. Mean rainfall during the nestling period has increased by 9.3 ± 0.3 mm decade
−1
, potentially explaining declining nestling body mass and population declines. Therefore, we suggest that reduced food availability, distinct from food abundance, may be an important and previously overlooked consequence of climate change, which could be affecting populations of species that specialize on foraging on flying insects.
A comparison of two mathematical models of the cerebrospinal fluid dynamics
Authors: Donatelli Donatella , Marcati Pierangelo , Romagnoli Licia
Published: March 2019

In this paper we provide the numerical simulations of two cerebrospinal fluid dynamics models by comparing our results with the real data available in literature (see Section 4). The models describe different processes in the cerebrospinal fluid dynamics: the cerebrospinal flow in the ventricles of the brain and the reabsorption of the fluid. In the appendix we show in detail the mathematical analysis of both models and we identify the set of initial conditions for which the solutions of the systems of equations do not exhibit blow up. We investigate step by step the accuracy of these theoretical outcomes with respect to the real cerebrospinal physiology and dynamics.

The plan of the paper is provided in Section 1.5.
Phylogenetic reclassification of vertebrate melatonin receptors to include Mel1d
Authors: Denker Elsa , Ebbesson Lars O. E. , Hazlerigg David G. , Macqueen Daniel J.
Published: March 2019

The circadian and seasonal actions of melatonin are mediated by high affinity G-protein coupled receptors (melatonin receptors, MTRs), classified into phylogenetically distinct subtypes based on sequence divergence and pharmacological characteristics. Three vertebrate MTR subtypes are currently described: MT1 (MTNR1A), MT2 (MTNR1B), and Mel1c (MTNR1C / GPR50), which exhibit distinct affinities, tissue distributions and signaling properties. We present phylogenetic and comparative genomic analyses supporting a revised classification of the vertebrate MTR family. We demonstrate four ancestral vertebrate MTRs, including a novel molecule hereafter named Mel1d. We reconstructed the evolution of each vertebrate MTR, detailing genetic losses in addition to gains resulting from whole genome duplication events in teleost fishes. We show that Mel1d was lost separately in mammals and birds and has been previously mistaken for an MT1 paralogue. The genetic and functional diversity of vertebrate MTRs is more complex than appreciated, with implications for our understanding of melatonin actions in different taxa. The significance of our findings, including the existence of Mel1d, are discussed in an evolutionary and functional context accommodating a robust phylogenetic assignment of MTR gene family structure.
A genetically adaptable strategy for ribose scavenging in a human gut symbiont plays a diet-dependent role in colon colonization
Authors: Glowacki Robert W. P. , Pudlo Nicholas A. , Tuncil Yunus , Luis Ana S. , Terekhov Anton I. , Hamaker Bruce R. , Martens Eric C.
Published: March 2019

Efficient nutrient acquisition in the competitive human gut is essential for microbial persistence. While polysaccharides have been well-studied nutrients for the gut microbiome, other resources such as co-factors and nucleic acids have been less examined. We describe a series of ribose utilization systems (RUSs) that are broadly represented in Bacteroidetes and appear to have diversified to allow access to ribose from a variety of substrates. OneBacteroides thetaiotaomicronRUS variant is critical for competitive gut colonization in a diet-specific fashion. Using molecular genetics, we probed the nature of the ribose source underlying this diet-specific phenotype, revealing that hydrolytic functions in RUS (e.g., to cleave ribonucleosides) are present but dispensable. Instead, ribokinases that are activatedin vivoand participate in cellular ribose-phosphate metabolism are essential. Our results underscore the extensive mechanisms that gut symbionts have evolved to access nutrients and how metabolic context determines the impact of these functionsin vivo.
Non-lethal exposure to H2O2 boosts bacterial survival and evolvability against oxidative stress
Authors: Rodríguez-Rojas Alexandro , Kim Joshua Jay , Johnston Paul , Makarova Olga , Eravci Murat , Weise Christoph , Hengge Regine , Rolff Jens
Published: March 2019

Unicellular organisms have the prevalent challenge to survive under oxidative stress of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). ROS are present as by-products of photosynthesis and aerobic respiration. These reactive species are even employed by multicellular organisms as potent weapons against microbes. Although bacterial defences against lethal and sub-lethal oxidative stress have been studied in model bacteria, the role of fluctuating H2O2 concentrations remains unexplored. It is known that sub-lethal exposure of Escherichia coli to H2O2 results in enhanced survival upon subsequent exposure. Here we investigate the priming response to H2O2 at physiological concentrations. The basis and the duration of the response (memory) were also determined by time-lapse quantitative proteomics. We found that a low level of H2O2 induced several scavenging enzymes showing a long half-life, subsequently protecting cells from future exposure. We then asked if the phenotypic resistance against H2O2 alters the evolution of resistance against oxygen stress. Experimental evolution of H2O2 resistance revealed faster evolution and higher levels of resistance in primed cells. Several mutations were found to be associated with resistance in evolved populations affecting different loci but, counterintuitively, none of them was directly associated with scavenging systems. Our results have important implications for host colonisation and infections where microbes often encounter reactive oxygen species in gradients.
TrackUSF, a novel methodology for automated analysis of ultrasonic vocalizations, reveals modified social communication in a rat model of autism
Authors: Netser Shai , Nahardiya Guy , Weiss-Dicker Gili , Dadush Roei , Goussha Yizhaq , Harony-Nicolas Hala , Cohen Lior , Crammer Kobi , Wagner Shlomo
Published: March 2019

Rodents emit various social ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interaction. USVs are usually analyzed by manual or semi-automated methodologies categorizing discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders effective use of USVs for screening animal models of human pathologies associated with modified social behavior, such as autism spectrum disorder (ASD). Here we present a novel, automated methodology for analyzing USVs, termed TrackUSF. To validate TrackUSF, we analyzed a dataset of mouse mating calls and compared the results with a manual analysis by a trained observer. We found that TrackUSF was capable of detecting most USVs, with less than 1% of false-positive detections. We then employed TrackUSF to social vocalizations in Shank3-deficient rats, a rat model of ASD and found, for the first time, that these vocalizations exhibit a spectrum of deviations from pro-social calls towards aggressive calls.
The roles of microtubules and membrane tension in axonal beading, retraction, and atrophy
Authors: Datar Anagha , Ameeramja Jaishabanu , Bhat Alka , Srivastava Roli , Bernal Roberto , Prost Jacques , Callan-Jones Andrew , Pullarkat Pramod A
Published: March 2019

Axonal beading—formation of a series of swellings along the axon—and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimer’s, Parkinson, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here we report controlled experiments which can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation vis à vis beading or retraction. Elucidating the mechanisms of these shape transformations will facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.
NGF-mediated photoablation of nociceptors reduces pain behavior in mice
Authors: Nocchi L , Portulano C , Franciosa F , Doleshall B , Panea M , Roy N , Maffei M , Gargano A , Perlas E , Heppenstall PA
Published: March 2019

Nerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here we describe novel technology to selectively photoablate TrkA positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near infrared (NIR) illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic and joint pain. To target peripheral nociceptors we generated a SNAP-tagged NGF derivative, NGFR121Wthat binds to TrkA/p75 receptors but does not provoke signaling in TrkA positive cells or elicit pain behaviors in mice. NGFR121W-SNAPwas coupled to the photosensitizer IRDye®700DX phthalocyanine (IR700) and injected subcutaneously. Following NIR illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic and neuropathic pain, mechanical hypersensitivity was abolished for three weeks following a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then re-innervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGFR121W-SNAP-mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.
Lumen expansion facilitates epiblast-primitive endoderm fate specification in the mouse blastocyst formation
Authors: Ryan Allyson Quinn , Chan Chii Jou , Graner François , Hiiragi Takashi
Published: March 2019

Mouse blastocyst formation involves lumen formation and cell fate specification. While many studies have investigated how the blastocyst cell lineages are specified through genetics and signaling, studies into the potential role of the fluid lumen have yet to be conducted. We discover that blastocyst fluid emerges by secretion of cytoplasmic vesicles to intercellular space in addition to trans-epithelial flow. We observe that the beginning of epiblast and primitive endoderm spatial segregation directly follows lumen coalescence. Notably, we show that perturbing lumen expansion by pharmacological and biophysical means impair the specification and spatial segregation of primitive endoderm cells within the blastocyst. Combined, our results suggest that blastocyst lumen expansion plays a critical role in guiding cell fate specification and positioning. As epithelial tissues typically form lumina, lumen expansion may provide a general mechanism of cell fate control in many tissues.
Deep Learning on Chaos Game Representation for Proteins
Authors: Löchel Hannah F. , Eger Dominic , Sperlea Theodor , Heider Dominik
Published: March 2019

Classification of protein sequences is one big task in bioinformatics and has many applications. Different machine learning methods exist and are applied on these problems, such as support vector machines (SVM), random forests (RF), and neural networks (NN). All of these methods have in common that protein sequences have to be made machine-readable and comparable in the first step, for which different encodings exist. These encodings are typically based on physical or chemical properties of the sequence. However, due to the outstanding performance of deep neural networks (DNN) on image recognition, we used frequency matrix chaos game representation (FCGR) for encoding of protein sequences into images. In this study, we compare the performance of SVMs, RFs, and DNNs, trained on FCGR encoded protein sequences. While the original chaos game representation (CGR) has been used mainly for genome sequence encoding and classification, we modified it to work also for protein sequences, resulting in n-flakes representation, an image with several icosagons.

We could show that all applied machine learning techniques (RF, SVM, and DNN) show promising results compared to the state-of-the-art methods on our benchmark datasets, with DNNs outperforming the other methods and that FCGR is a promising new encoding method for protein sequences.
Direct Sequencing of RNA with MinION Nanopore: Detecting Mutations based on Associations
Authors: Harel Noam , Meir Moran , Gophna Uri , Stern Adi
Published: March 2019

One of the key challenges in the field of genetics is the inference of haplotypes from next generation sequencing data. The MinION Oxford Nanopore sequencer allows sequencing long reads, with the potential of sequencing complete genes, and even complete genomes of viruses, in individual reads. However, MinION suffers from high error rates, rendering the detection of true variants difficult. Here we propose a new statistical approach named AssociVar, which differentiates between true mutations and sequencing errors from direct RNA/DNA sequencing using MinION. Our strategy relies on the assumption that sequencing errors will be dispersed randomly along sequencing reads, and hence will not be associated with each other, whereas real mutations will display a non-random pattern of association with other mutations. We demonstrate our approach using direct RNA sequencing data from evolved populations of the MS2 bacteriophage, whose small genome makes it ideal for MinION sequencing. AssociVar inferred several mutations in the phage genome, which were corroborated using parallel Illumina sequencing. This allowed us to reconstruct full genome viral haplotypes constituting different strains that were present in the sample. Our approach is applicable to long read sequencing data from any organism for accurate detection of bona fide mutations and inter-strain polymorphisms.
Single and population coding of taste in the gustatory-cortex of awake mice
Authors: Levitan David , Lin Jian-You , Wachutka Joseph , Mukherjee Narendra , Nelson Sacha B. , Katz Donald B.
Published: March 2019

Electrophysiological analysis has reveals much about the broad coding and neural ensemble dynamics that characterize gustatory cortical (GC) taste processing in awake rats, and about how these dynamics relate to behavior. With regard to mice, meanwhile, data concerning cortical taste coding have largely been restricted to imaging—a technique that reveals average levels of neural responsiveness, but that (currently) lacks the temporal sensitivity necessary for evaluation of fast response dynamics; furthermore, the few extant studies have thus far failed to provide consensus on basic features of coding. We have recorded the spiking activity of ensembles of GC neurons while presenting representatives of the basic taste modalities (sweet, salty, sour and bitter) to awake mice. Our first central result is the identification of similarities between rat and mouse taste processing: most mouse GC neurons (~66%) responded distinctly to multiple (3-4) tastes; temporal coding analyses further reveal, for the first time, that single mouse GC neurons sequentially code taste identity and palatability—the latter responses emerging ~0.5s after the former—with whole GC ensembles transitioning suddenly and coherently from coding taste identity to coding taste palatability. The second finding is that spatial location plays very little role in any aspect of taste responses—neither between- (anterior-posterior) nor within-mouse (dorsal-ventral) mapping revealed anatomical regions with narrow or temporally simple taste responses. These data confirm recent results showing that mouse cortical taste responses are not “gustatopic,” but also go beyond these imaging results to show that mice process tastes through time.
Context-specific effects of facial dominance and trustworthiness on hypothetical leadership decisions
Authors: Ferguson Hannah S. , Owen Anya , Hahn Amanda C. , Torrance Jaimie , DeBruine Lisa M. , Jones Benedict C.
Published: March 2019

Social judgments of faces predict important social outcomes, including leadership decisions. Previous work suggests that facial cues associated with perceptions of dominance and trustworthiness have context-specific effects on leadership decisions. Facial cues linked to perceived dominance have been found to be preferred in leaders for hypothetical wartime contexts and facial cues linked to perceived trustworthiness have been found to be preferred in leaders for hypothetical peacetime contexts. Here we sought to replicate these effects using images of women’s faces. Consistent with previous work, a linear mixed effects model demonstrated that more trustworthy-looking faces were preferred in leaders during times of peace and more dominant-looking faces were preferred in leaders during times of war. These results provide converging evidence for context-specific effects of facial cues on hypothetical leadership judgments.
Supra-threshold perception and neural representation of tones presented in noise in conditions of masking release
Authors: Egger Katharina , Dau Torsten , Epp Bastian
Published: March 2019

The neural representation and perceptual salience of tonal signals presented in different noise maskers were investigated. The properties of the maskers and signals were varied such that they produced different amounts of either monaural masking release, binaural masking release, or a combination of both. The signals were then presented at different levels above their corresponding masked thresholds and auditory evoked potentials (AEPs) were measured. It was found that, independent of the masking condition, the amplitude of the P2 component of the AEP was similar for the same stimulus levels above masked threshold, suggesting that both monaural and binaural effects of masking release were represented at the level of P2 generation. The perceptual salience of the signal was evaluated at equal levels above masked threshold using a rating task. In contrast to the electrophysiological findings, the subjective ratings of the perceptual signal salience were less consistent with the signal level above masked threshold and varied strongly across listeners and masking conditions. Overall, the results from the present study suggest that the P2 amplitude of the AEP represents an objective indicator of the audibility of a target signal in the presence of complex acoustic maskers.
The microbiota regulates inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination
Authors: McMurran Christopher E , de la Fuente Alerie Guzman , Penalva Rosana , Menachem-Zidon Ofra Ben , Dombrowski Yvonne , Gonzalez Ginez A , Zhao Chao , Krause Fynn N , Young Adam MH , Griffin Julian L , Jones Clare A , Hollins Claire , Heimesaat Markus M , Fitzgerald Denise C , Franklin Robin JM
Published: March 2019

The microbiota is now recognised as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress towards therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination – the regeneration of myelin sheaths – also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics negatively influence remyelination and further our understanding of how mammalian regeneration relates to the microbiota.
Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches
Authors: Treveil A , Sudhakar P , Matthews Z J , Wrzesinski T , Jones E J , Brooks J , Olbei M , Hautefort I , Hall L J , Carding S R , Mayer U , Powell P P , Wileman T , Di Palma F , Haerty W , Korcsmáros T
Published: March 2019

The epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3Din vitrocultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long non-coding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn’s disease or ulcerative colitis.

Table of contents

We demonstrate the application of network biology techniques to increase understanding of intestinal dysbiosis through studying transcriptomics data from Paneth and goblet cell enriched enteroids.
The Aspartic Protease Ddi1 Contributes to DNA-Protein Crosslink Repair in Yeast
Authors: Serbyn Nataliia , Noireterre Audrey , Bagdiul Ivona , Plank Michael , Michel Agnès H , Loewith Robbie , Kornmann Benoît , Stutz Françoise
Published: March 2019

Naturally occurring or drug-induced DNA-protein crosslinks (DPCs) interfere with key DNA transactions if not timely repaired. The unique family of DPC-specific proteases Wss1/SPRTN targets DPC protein moieties for degradation, including topoisomerase-1 trapped in covalent crosslinks (Top1ccs). Here we describe that the efficient DPC disassembly requires Ddi1, another conserved predicted protease in Saccharomyces cerevisiae. We found Ddi1 in a genetic screen of the tdp1wss1 mutant defective in Top1cc processing. Ddi1 is recruited to a persistent Top1cc-like DPC lesion in an S-phase dependent manner to assist eviction of crosslinked protein from DNA. Loss of Ddi1 or its putative protease activity hypersensitize cells to DPC trapping agents independently from Wss1 and 26S proteasome, implying its broader role in DPC repair. Among potential Ddi1 targets we found the core component of RNAP II and show that its genotoxin-induced degradation is impaired in ddi1. Together, we propose that the Ddi1 protease contributes to DPC proteolysis.
Decentralized Distribution-sampled Classification Models with Application to Brain Imaging
Authors: Lewis Noah , Gazula Harshvardhan , Plis Sergey M. , Calhoun Vince D.
Published: March 2019

0.1

background

In this age of big data, large data stores allow researchers to compose robust models that are accurate and informative. In many cases, the data are stored in separate locations requiring data transfer between local sites, which can cause various practical hurdles, such as privacy concerns or heavy network load. This is especially true for medical imaging data, which can be constrained due to the health insurance portability and accountability act (HIPAA). Medical imaging datasets can also contain many thousands or millions of features, requiring heavy network load.

0.2

New Method

Our research expands upon current decentralized classification research by implementing a new singleshot method for both neural networks and support vector machines. Our approach is to estimate the statistical distribution of the data at each local site and pass this information to the other local sites where each site resamples from the individual distributions and trains a model on both locally available data and the resampled data.

0.3

Results

We show applications of our approach to handwritten digit classification as well as to multi-subject classification of brain imaging data collected from patients with schizophrenia and healthy controls. Overall, the results showed comparable classification accuracy to the centralized model with lower network load than multishot methods.

0.4

Comparison with Existing Methods

Many decentralized classifiers are multishot, requiring heavy network traffic. Our model attempts to alleviate this load while preserving prediction accuracy.

0.5

Conclusions

We show that our proposed approach performs comparably to a centralized approach while minimizing network traffic compared to multishot methods.

0.6

Highlights

A novel yet simple approach to decentralized classification

Reduces total network load compared to current multishot algorithms

Maintains a prediction accuracy comparable to the centralized approach
Pore-modulating toxins exploit inherent slow inactivation to block K+channels
Authors: Karbat Izhar , Altman-Gueta Hagit , Fine Shachar , Szanto Tibor , Hamer-Rogotner Shelly , Dym Orly , Frolow Felix , Gordon Dalia , Panyi Gyorgy , Gurevitz Michael , Reuveny Eitan
Published: March 2019

Voltage dependent potassium channels (Kvs) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K+-selective pore. Animal toxins targeting Kvs are classified to “pore-blockers” that physically plug the ion conduction pathway and “gating modifiers” that disrupt voltage sensor movements. A third group of toxins blocks K+conduction by an unknown mechanism via binding to the channel turrets. Here we show that Cs1, a peptide toxin isolated from cone snail venom, binds at the turrets of Kv1.2 and targets a network of hydrogen bonds that govern water access to the peripheral cavities that surround the central pore. The resulting ectopic water flow triggers an asymmetric collapse of the pore by a process resembling that of inherent slow inactivation. Pore modulation by animal toxins exposes the peripheral cavity of K+channels as a novel pharmacological target and provides a rational framework for drug design.
Accessible and interactive RNA sequencing analysis using serverless computing
Authors: Hung Ling-Hong , Niu Xingzhi , Lloyd Wes , Yeung Ka Yee
Published: March 2019

We present a novel method that yields 1100-fold computational speedup and allows biomedical scientists to interactively adjust alignment parameters in real time to iteratively improve final analytical results. Specifically, the alignment time for a 640 million read human RNA-sequencing dataset is reduced from 19 hours to 1 minute using serverless cloud computing. We provide a graphical interface for the accelerated workflows, thus making our methodology accessible to non-cloud experts.
A Bayesian Approach for Inferring the Impact of a Discrete Character on Rates of Continuous-Character Evolution in the Presence of Background-Rate Variation
Authors: May Michael R. , Moore Brian R.
Published: March 2019

Understanding how and why rates of character evolution vary across the Tree of Life is central to many evolutionary questions; e.g., does the trophic apparatus (a set of continuous characters) evolve at a higher rate in fish lineages that dwell in reef versus non-reef habitats (a discrete character)? Existing approaches for inferring the relationship between a discrete character and rates of continuous-character evolution rely on comparing a null model (in which rates of continuous-character evolution are constant across lineages) to an alternative model (in which rates of continuous-character evolution depend on the state of the discrete character under consideration). However, these approaches are susceptible to a “straw-man” effect: the influence of the discrete character is inflated because the null model is extremely unrealistic. Here, we describe MuSSCRat, a Bayesian approach for inferring the impact of a discrete trait on rates of continuous-character evolution in the presence of alternative sources of rate variation (“background-rate variation”). We demonstrate by simulation that our method is able to reliably infer the degree of state-dependent rate variation, and show that ignoring background-rate variation leads to biased inferences regarding the degree of state-dependent rate variation in grunts (the fish group Haemulidae). [continuous-character evolution; discrete-character evolution; Bayesian phylogenetic comparative methods; data augmentation]