bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifractal nature of chromosome contact maps
Authors: Pigolotti Simone , Jensen Mogens H. , Zhan Yinxiu , Tiana Guido
Published: June 2019

Modern biological techniques such as Hi–C permit to measure probabilities that different chromosomal regions are close in space. These probabilities can be visualised as matrices called contact maps. In this paper, we introduce a multifractal analysis of chromosomal contact maps. Our analysis reveals that Hi–C maps are bifractal, i.e. complex geometrical objects characterized by two distinct fractal dimensions. To rationalize this observation, we introduce a model that describes chromosomes as a hierarchical set of nested domains and we solve it exactly. The predicted multifractal spectrum is in excellent quantitative agreement with experimental data. Moreover, we show that our theory yields to a more robust estimation of the scaling exponent of the contact probability than existing methods. By applying this method to experimental data, we detect subtle conformational changes among chromosomes during differentiation of human stem cells.
Streptolysin production and activity is central toin vivopathotype and disease outcome in GAS infections
Authors: Clarke Jenny , Baltazar Murielle , Alsahag Mansoor , Panagiotou Stavros , Pouget Marion , Paxton William A , Pollakis Georgios , Everett Dean , French Neil , Kadioglu Aras
Published: June 2019

Streptococcus pyogenes (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcomein vivo, by using two different clinical lineages; the recently emerged hypervirulent outbreakemmtype 32.2 strains, which result in sepsis, and theemmtype 1.0 strains which cause septic arthritis. Using clinically relevantin vivomouse models of sepsis and a novel septic arthritis model, we demonstrated that the amount and activity of SLO is vital in determining the pathotype of infection. Theemm32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the lower levels and haemolytic activity ofemm1.0 SLO led to translocation of bacteria to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key toin vivopathotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.
Enhanced inference of ecological networks by parameterizing ensembles of population dynamics models constrained with prior knowledge
Authors: Liao Chen , Xavier Joao B. , Zhu Zhenduo
Published: June 2019

Background

Accurate network models of species interaction could be used to predict population dynamics and be applied to manage real world ecosystems. Most relevant models are nonlinear, however, and data available from real world ecosystems are too noisy and sparsely sampled for common inference approaches. Here we improved the inference of generalized Lotka-Volterra (gLV) ecological networks by using a new optimization algorithm to constrain parameter signs with prior knowledge and a perturbation-based ensemble method.

Results

We applied the new inference to long-term species abundance data from the freshwater fish community in the Illinois River, United States. We constructed an ensemble of 668 gLV models that explained 79% of the data on average. The models indicated (at a 70% level of confidence) a strong positive interaction from emerald shiner (Notropis atherinoides) to channel catfish (Ictalurus punctatus), which we could validate using data from a nearby observation site, and predicted that the relative abundances of most fish species will continue to fluctuate temporally and concordantly in the near future. The network shows that the invasive silver carp (Hypophthalmichthys molitrix) has much stronger impacts on native predators than on prey, supporting the notion that the invader perturbs the native food chain by replacing the diets of predators.

Conclusions

Ensemble approaches constrained by prior knowledge can improve inference and produce networks from noisy and sparsely sampled time series data to fill knowledge gaps on real world ecosystems. Such network models could aid efforts to conserve ecosystems such as the Illinois River, which is threatened by the invasion of the silver carp.
Automated characterization of noise distributions in diffusion MRI data
Authors: St-Jean Samuel , De Luca Alberto , Tax Chantal M. W. , Viergever Max A. , Leemans Alexander
Published: June 2019

Knowledge of the noise distribution in magnitude diffusion MRI images is the centerpiece to quantify uncertainties arising from the acquisition process. The use of parallel imaging methods, the number of receiver coils and imaging filters applied by the scanner, amongst other factors, dictate the resulting signal distribution. Accurate estimation beyond textbook Rician or noncentral chi distributions often requires information about the acquisition process (e.g., coils sensitivity maps or reconstruction coeffcients), which is usually not available. We introduce two new automated methods using the moments and maximum likelihood equations of the Gamma distribution to estimate noise distributions as they explicitly depend on the number of coils, making it possible to estimate all unknown parameters using only the magnitude data. A rejection step is used to make the framework automatic and robust to artifacts. Simulations using stationary and spatially varying noncentral chi noise distributions were created for two diffusion weightings with SENSE or GRAPPA reconstruction and 8, 12 or 32 receiver coils. Furthermore, MRI data of a water phantom with different combinations of parallel imaging were acquired on a 3T Philips scanner along with noise-only measurements. Finally, experiments on freely available datasets from a single subject acquired on a 3T GE scanner are used to assess reproducibility when limited information about the acquisition protocol is available. Additionally, we demonstrated the applicability of the proposed methods for a bias correction and denoising task on an in vivo dataset acquired on a 3T Siemens scanner. A generalized version of the bias correction framework for non integer degrees of freedom is also introduced. The proposed framework is compared with three other algorithms with datasets from three vendors, employing different reconstruction methods. Simulations showed that assuming a Rician distribution can lead to misestimation of the noise distribution in parallel imaging. Results on the acquired datasets showed that signal leakage in multiband can also lead to a misestimation of the noise distribution. Repeated acquisitions of in vivo datasets show that the estimated parameters are stable and have lower variability than compared methods. Results for the bias correction and denoising task show that the proposed methods reduce the appearance of noise at high b-value. The proposed algorithms herein can estimate both parameters of the noise distribution automatically, are robust to signal leakage artifacts and perform best when used on acquired noise maps.
The intracellular symbiont Wolbachia enhances recombination in a dose-dependent manner
Authors: Bryant Kaeli N. , Newton Irene L.G.
Published: June 2019

Wolbachia pipientis is an intracellular alphaproteobacterium that infects 40-60% of insect species and is well known for host reproductive manipulations. Although Wolbachia are primarily maternally transmitted, evidence of horizontal transmission can be found in incongruent host-symbiont phylogenies and recent acquisitions of the same Wolbachia strain by distantly related species. Parasitoids and predator-prey interactions may indeed facilitate the transfer of Wolbachia between insect lineages but it is likely that Wolbachia are acquired via introgression in many cases. Many hypotheses exist as to explain Wolbachia prevalence and penetrance such as nutritional supplementation, protection from parasites, protection from viruses, or straight up reproductive parasitism. Using classical genetics we show that Wolbachia increase recombination in infected lineages across two genomic intervals. This increase in recombination is titer dependent as the wMelPop variant, which infects at higher load in Drosophila melanogaster, increases recombination 5% more than the wMel variant. In addition, we also show that Spiroplasma poulsonii, the other bacterial intracellular symbiont of Drosophila melanogaster, does not induce an increase in recombination. Our results suggest that Wolbachia infection specifically alters host recombination landscape in a dose dependent manner.

Article Summary

The ubiquitous bacterial symbiont Wolbachia is known to alter host reproduction through manipulation of host cell biology, protect from pathogens, and supplement host nutrition. In this work we show that Wolbachia specifically increases host recombination in a dose dependent manner. Flies harboring Wolbachia exhibit elevated rates of recombination across the 2nd and X chromosomes and this increase is proportional to their Wolbachia load. In contrast, another intracellular symbiont, Spiroplasma, does not lead to an increase in recombination across the intervals tested. Our results point to a specific effect of Wolbachia infection that may have a significant effect on infected insect populations.
Classification of human physical activity based on the raw accelerometry data via spherical coordinate transformation
Authors: Kos Michał , Bogdan Małgorzata , Glynn Nancy W. , Harezlak Jaroslaw
Published: June 2019

Human health is strongly associated with person’s lifestyle and levels of physical activity. Therefore, characterization of daily human activity is an important task. Accelerometers have been used to obtain precise measurements of body acceleration. Wearable accelerometers collect data as a three-dimensional time series with frequencies up to 100Hz. Using such accelerometry signal, we are able to classify different types of physical activity.

In our work, we present a novel procedure for physical activity classification based on the raw accelerometry signal. Our proposal is based on the spherical representation of the data. We classify four activity types: resting, upper body activities (sitting), upper body activities (standing) and lower body activities. The classifier is constructed using decision trees with extracted features consisting of spherical coordinates summary statistics, moving averages of the radius and the angles, radius variance and spherical variance.

The classification accuracy of our method has been tested on data collected on a sample of 47 elderly individuals who performed a series of activities in laboratory settings. The achieved classification accuracy is over 90% when the subject-specific data are used and 84% when the group data are used. Main contributor to the classification accuracy is the angular part of the collected signal, especially spherical variance. To the best of our knowledge, spherical variance has never been previously used in the analysis of the raw accelerometry data. Its major advantage over other angular measures is its invariance to the accelerometer location shifts.
Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson’s disease
Authors: Brown EE , Blauwendraat C , Trinh J , Rizig M , Nalls MA , Leveille E , Ruskey JA , Jonvik H , Tan MMX , Bandres-Ciga S , Hassin-Baer S , Brockmann K , Infante J , Tolosa E , Ezquerra M , Benromdhan S , Benmahdjoub M , Hardy J , Singleton AB , Alcalay RN , Gasser T , Grosset D , Williams NM , Pittman A , Gan-Or Z , Fernandez-Santiago R , Brice A , Lesage S , Farrer M , Wood N , Morris HR ,   on behalf of the International Parkinson Disease Genomics Consortium (IPDGC)
Published: June 2019

Objective

To assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk alleles

Methods

We analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).

Results

There was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).

Interpretation

Analysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.
Enabling Semantic Queries Across Federated Bioinformatics Databases
Authors: Sima Ana Claudia , de Farias Tarcisio Mendes , Zbinden Erich , Anisimova Maria , Gil Manuel , Stockinger Heinz , Stockinger Kurt , Robinson-Rechavi Marc , Dessimoz Christophe
Published: June 2019

Motivation

Data integration promises to be one of the main catalysts in enabling new insights to be drawn from the wealth of biological data available publicly. However, the heterogeneity of the different data sources, both at the syntactic and the semantic level, still poses significant challenges for achieving interoperability among biological databases.

Results

We introduce an ontology-based federated approach for data integration. We applied this approach to three heterogeneous data stores that span different areas of biological knowledge: 1) Bgee, a gene expression relational database; 2) OMA, a Hierarchical Data Format 5 (HDF5) orthology data store, and 3) UniProtKB, a Resource Description Framework (RDF) store containing protein sequence and functional information. To enable federated queries across these sources, we first defined a new semantic model for gene expression called GenEx. We then show how the relational data in Bgee can be expressed as a virtual RDF graph, instantiating GenEx, through dedicated relational-to-RDF mappings. By applying these mappings, Bgee data are now accessible through a public SPARQL endpoint. Similarly, the materialised RDF data of OMA, expressed in terms of the Orthology ontology, is made available in a public SPARQL endpoint. We identified and formally described intersection points (i.e. virtual links) among the three data sources. These allow performing joint queries across the data stores. Finally, we lay the groundwork to enable nontechnical users to benefit from the integrated data, by providing a natural language template-based search interface.

Project URL

http://biosoda.expasy.org, https://github.com/biosoda/bioquery
Molecular and cellular correlates of human nerve regeneration: ADCYAP1 encoding PACAP enhances sensory neuron outgrowth
Authors: Schmid Annina B , Baskozos Georgios , Windsor Katherine , Karlsson Pall , Sandy-Hindmarch Oliver , Weir Greg A , McDermott Lucy A , Clark Alex J , Burchall Joanna , Wiberg Akira , Furniss Dominic , Bennett David LH
Published: June 2019

We only have a rudimentary understanding of the molecular and cellular determinants of human nerve regeneration. Here, we use carpal tunnel syndrome (CTS) as a human model system to prospectively evaluate correlates of neural regeneration and their relationship with clinical recovery after decompression surgery. At 6 months post-surgery, we noted a significant improvement of median nerve neurophysiological and somatosensory function. Serial skin biopsies revealed a partial recovery of intraepidermal innervation, whose extent correlated with symptom improvement. In myelinated afferents, nodal length increased postoperatively. Transcriptional profiling of the skin revealed 23 differentially expressed genes following decompression, with ADCYAP1 (encoding PACAP) being the most strongly upregulated and showing an association with regeneration of intraepidermal nerve fibres. Using human induced pluripotent stem cell-derived sensory neurons, we confirmed that PACAP significantly enhances axon outgrowth in vivo. Since PACAP signals through G-protein receptors, this pathway provides an interesting therapeutic target for human sensory nerve regeneration.
Mouse retinal cell behaviour in space and time using light sheet fluorescence microscopy
Authors: Prahst Claudia , Ashrafzadeh Parham , Harrington Kyle , Venkatraman Lakshmi , Richards Mark , Russo Ana Martins , Cho Kin-Sang , Chang Karen , Mead Thomas , Chen Dong Feng , Richardson Douglas , Claesson-Welsh Lena , Franco Claudio , Bentley Katie
Published: June 2019

As the general population ages and the incidence of diabetes increases epidemically, more people are affected by eye diseases, such as retinopathies. It is therefore critical to improve imaging of eye disease mouse models. Here, we demonstrate that 1) rapid, quantitative 3D and 4D (time lapse) imaging of cellular and subcellular processes in the murine eye is feasible, with and without tissue clearing, using light-sheet fluorescent microscopy (LSFM) and 2) LSFM readily reveals new features of even well studied eye disease mouse models, such as the Oxygen-Induced Retinopathy (OIR) model. Through correlative LSFM-Confocal imaging we find that flat-mounting retinas for confocal microscopy significantly distorts tissue morphology. The minimized distortion with LSFM dramatically improved analysis of pathological vascular tufts in the OIR model revealing “knotted” morphologies, leading to a proposed new tuft nomenclature. Furthermore, live-imaging of OIR tuft formation revealed abnormal cell motility and altered filopodia dynamics. We conclude that quantitative 3D/4D LSFM imaging and analysis has the potential to advance our understanding of pathological processes in the eye, in particular neuro-vascular degenerative processes.
Direct evidence for transport of RNA from the mouse brain to the germline and offspring
Authors: O’Brien Elizabeth A. , Ensbey Kathleen S. , Day Bryan W. , Baldock Paul A. , Barry Guy
Published: June 2019

Background

The traditional concept that heritability occurs exclusively from the transfer of germline-restricted genetics is being challenged by the increasing accumulation of evidence confirming the existence of experience-dependent transgenerational inheritance. However, questions remain unanswered as to how heritable information can be passed from somatic cells. Previous studies have implicated the critical involvement of RNA in heritable transgenerational effects and the high degree of mobility and genomic impact of RNAs in all organisms is an attractive model for the efficient transfer of genetic information.

Results

We hypothesized that RNA may be transported from a somatic tissue, in this case the brain, of an adult male mouse to the germline, and subsequently to offspring. To investigate this, we injected one hemisphere of the male mouse striatum with an AAV1/9 virus expressing human pre-MIR941 (MIR941). After 2, 8 and 16 weeks following injection, we used an LNA-based qPCR system to detect the presence of virus and human MIR941 in brain, peripheral tissues and offspring, from injected male mice mated with uninjected females. Virus was never detected outside of the brain. Verification of single bands of the correct size for MIR941 was performed using Sanger sequencing while quantitation demonstrated that a small percentage (∼ 1-8%) of MIR941 is transported to the germline and to offspring in about a third of the cases.

Conclusions

We show that somatic RNA can be transported to the germline and passed on to offspring, thereby providing additional evidence of a role for RNA in somatic cell-derived transgenerational effects.
Single-particle measurements of filamentous influenza virions reveal damage induced by freezing
Authors: Hirst Jack C. , Hutchinson Edward C.
Published: June 2019

Clinical isolates of influenza virus produce pleiomorphic virions, ranging from small spheres to elongated filaments. The filaments are seemingly adaptive in natural infections, but their basic functional properties are poorly understood and functional studies of filaments often report contradictory results. This may be due to artefactual damage from routine laboratory handling, an issue which has been noted several times without being explored in detail. To determine whether standard laboratory techniques could damage filaments, we used immunofluorescence microscopy to rapidly and reproducibly quantity and characterise the dimensions of filaments. Most of the techniques we tested had minimal impact on filaments, but freezing to -70°C, a standard storage step before carrying out functional studies on influenza viruses, severely reduced both their concentration and median length. We noted that damage from freezing is likely to have affected most of the functional studies of filaments performed to date, and to address this we show that it can be mitigated by using the cryoprotectant DMSO. We recommend that functional studies of filaments characterise virion populations prior to analysis to ensure reproducibility, and that they use unfrozen samples if possible and cryoprotectants if not. These basic measures will support the robust functional characterisations of filaments that are required to understand their roles in natural influenza virus infections.
PDXGEM: Patient-Derived Tumor Xenograft based Gene Expression Model for Predicting Clinical Response to Anticancer Therapy in Cancer Patients
Authors: Kim Youngchul , Kim Daewon , Cao Biwei , Carvajal Rodrigo , Kim Minjung
Published: June 2019

Background

Cancer is a highly heterogeneous disease and shows varying responses to anti-cancer drugs. Although several approaches have been attempted to predict the drug responses by analyzing molecular profiling data of tumors from preclinical cancer models or cancer patients, there is still a great need of developing highly accurate prediction models of response to the anti-cancer drugs for clinical applications toward personalized medicine. Here, we present PDXGEM pipeline to build a predictive gene expression model (GEM) for cancer patients’ drug responses on the basis of data on gene expression and drug activity in patient-derived xenograft (PDX) models.

Results

Drug sensitivity biomarkers were identified by an association analysis between gene expression levels and post-treatment tumor volume changes in PDX models. Only biomarkers with concordant co-expression patterns between the PDX and cancer patient tumors were used in random-forest algorithm to build a drug response prediction model, so called PDXGEM. We applied PDXGEM to several cytotoxic chemotherapy as well as targeted therapy agents that are used to treat breast cancer, pancreatic cancer, colorectal cancer, or non-small cell lung cancer. Significantly accurate predictions of PDXGEM for pathological and survival outcomes were observed through extensive validation analyses of multiple independent cancer patient datasets obtained from retrospective observational study and prospective clinical trials.

Conclusion

Our results demonstrated a strong potential of utilizing molecular profiles and drug activity data of PDX tumors for developing a clinically translatable predictive cancer biomarkers for cancer patients. PDXGEM web application is publicly available athttp://pdxgem.moffitt.org.
Stress- and pathway-specific impacts of impaired jasmonoyl-isoleucine (JA-Ile) catabolism on defense signaling and biotic stress resistance in Arabidopsis
Authors: Marquis Valentin , Smirnova Ekaterina , Poirier Laure , Zumsteg Julie , Schweizer Fabian , Reymond Philippe , Heitz Thierry
Published: June 2019

Jasmonate (JA) synthesis and signaling are essential for plant defense upregulation upon herbivore or microbial attacks. Stress-induced accumulation of jasmonoyl-isoleucine (JA-Ile), the bioactive hormonal form triggering major transcriptional changes, is often dynamic and transient, due to the existence of potent removal mechanisms. Two distinct but interconnected JA-Ile turnover pathways have been described in Arabidopsis, either via cytochrome P450 (CYP94)-mediated oxidation, or through deconjugation by the amidohydrolases (AH) IAR3 and ILL6. Their impact was not well known because of gene redundancy and compensation mechanisms when each pathway was partially impaired. Here we address the consequences of fully blocking either or both pathways on JA homeostasis and defense signaling in three mutant backgrounds: a doubleiar3 ill6(2ah) mutant, a triplecyp94b1 b3 c1mutant (3cyp), and a newly generated quintuple (5ko) mutant deficient in all known JA-Ile-degrading activities. These lines behaved very differently in response to either mechanical wounding, insect attack or fungal infection, highlighting the stress-specific contributions and impacts of JA-Ile catabolic pathways. Deconjugation and oxidative pathways contributed additively to JA-Ile removal upon wounding, but their genetic impairement had opposite impacts onSpodoptera littoralislarvae feeding:2ahline was more resistant whereas3cypwas more susceptible to insect attack. In contrast,2ah, 5kobut not3cypoveraccumulated JA-Ile upon inoculation byBotrytis cinerea, yet3cypwas most resistant to the fungus. Despite of building-up unprecedented JA-Ile levels,5kodisplayed near WT levels of resistance in both bioassays. Molecular and metabolic analysis indicated that restrained JA-Ile catabolism resulted in enhanced defense and resistance levels only if genes encodingJAZorJAMnegative regulators were not simultaneously overstimulated. Our data demonstrate that despite of acting on a shared hormonal substrate, AH or/and CYP94 deficiency differentially impacts JA homeostasis, responses and tolerance to related biotic stresses.
Sexual selection does not increase the rate of compensatory adaptation to a mutation influencing a secondary sexual trait inDrosophila melanogaster
Authors: Chandler Christopher H. , Mammel Anna , Dworkin Ian
Published: June 2019

Theoretical work predicts that sexual selection can enhance natural selection, increasing the rate of adaptation to new environments and helping purge harmful mutations. While some experiments support these predictions, remarkably little work has addressed the role of sexual selection on compensatory adaptation—populations’ ability to compensate for the costs of deleterious alleles that are already present. We tested whether sexual selection, as well as the degree of standing genetic variation, affect the rate of compensatory evolution via phenotypic suppression in experimental populations ofDrosophila melanogaster. These populations were fixed for a spontaneous mutation causing mild abnormalities in the male sex comb, a structure important for mating success. We fine-mapped this mutation to an ∼85 kb region on the X chromosome containing three candidate genes, showed that the mutation is deleterious, and that its phenotypic expression and penetrance vary by genetic background. We then performed experimental evolution, including a treatment where opportunity for mate choice was limited by experimentally enforced monogamy. Although evolved populations did show some phenotypic suppression of the morphological abnormalities in the sex comb, the amount of suppression did not depend on the opportunity for sexual selection. Sexual selection, therefore, may not always enhance natural selection; instead, the interaction between these two forces may depend on additional factors.
Functional ultrasound speckle decorrelation-based velocimetry of the brain
Authors: Tang Jianbo , Postnov Dmitry D. , Kilic Kivilcim , Erdener Sefik Evren , Lee Blaire , Giblin John T. , Szabo Thomas L. , Boas David A.
Published: June 2019

A high-speed, contrast free, quantitative ultrasound velocimetry (vUS) for blood flow velocity imaging throughout the rodent brain is developed based on the normalized first order temporal autocorrelation function of the ultrasound field signal. vUS is able to quantify blood flow velocity in both transverse and axial directions, and is validated with numerical simulation, phantom experiments, and in vivo measurements. The functional imaging ability of vUS is demonstrated by monitoring blood flow velocity changes during whisker stimulation in awake mice. Compared to existing power Doppler and color Doppler-based functional ultrasound imaging techniques, vUS shows quantitative accuracy in estimating both axial and transverse flow speeds and resistance to acoustic attenuation and high frequency noise.
HP1γ binding pre-mRNA at intronic repeats increases splicing fidelity and regulates alternative exon usage
Authors: Rachez Christophe , Legendre Rachel , Costallat Mickaël , Varet Hugo , Yi Jia , Kornobis Etienne , Muchardt Christian
Published: June 2019

HP1 proteins are best known as markers of heterochromatin and gene silencing. Yet, they are also RNA-binding proteins and the HP1γ/Cbx3 family member is present on transcribed genes together with RNA polymerase II, where it regulates co-transcriptional processes such as alternative splicing. To gain insight in the role of the RNA binding activity of HP1γ in transcriptionally active chromatin, we have captured and analyzed RNAs associated with this protein. We find that HP1γ specifically recognizes hexameric RNA motifs and coincidentally transposable elements of the SINE family. As these elements are abundant in introns, while essentially absent from exons, the HP1γ RNA binding activity tethers unspliced pre-mRNA to chromatin via the intronic region and limits the usage of intronic cryptic splice sites. Thus, our data unveil novel determinants in the relationship between chromatin and co-transcriptional splicing.
Molecular estimation of neurodegeneration pseudotime in older brains
Authors: Mukherjee Sumit , Heath Laura , Preuss Christoph , Jayadev Suman , Garden Gwenn A. , Greenwood Anna K , Sieberts Solveig K , De Jager Phillip L , Ertekin-Taner Nilufer , Carter Gregory W , Mangravite Lara M , Logsdon Benjamin A
Published: June 2019

The temporal molecular changes that lead to disease onset and progression in Alzheimer’s disease are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage – or disease pseudotime - for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0×10−5), Aβ (CERAD score, P = 1.8×10−5), and cognitive diagnosis (P = 3.5×10−7) of LOAD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data.
Regulation of Numb during planar cell polarity establishment in the Drosophila eye
Authors: Domingos Pedro M , Jenny Andreas , del Alamo David , Mlodzik Marek , Steller Hermann , Mollereau Bertrand
Published: June 2019

The establishment of planar cell polarity (PCP) in theDrosophilaeye requires correct specification of the R3/R4 pair of photoreceptor cells, determined by a Frizzled mediated signaling event that specifies R3 and induces Delta to activate Notch signaling in the neighboring cell, specifying it as R4. Here, we investigated the role of the Notch signaling negative regulator Numb in the specification of R3/R4 fates and PCP establishment in theDrosophilaeye. We observed that Numb is transiently upregulated in R3 at the time of R3/R4 specification. This regulation of Numb levels in developing photoreceptors occurs at the post-transcriptional level and is dependent on Dishevelled, an effector of Frizzled signaling, and Lethal Giant Larva. We detected PCP defects in cells homozygous fornumb15, but these defects were due to a loss of function mutation infat(fatQ805*) being present in thenumb15chromosome. However, mosaic overexpression of Numb in R4 precursors (only) caused PCP defects andnumbloss-of-function had a modifying effect on the defects found in a hypomorphicdishevelledmutation. Our results suggest that Numb levels are upregulated to reinforce the bias of Notch signaling activation in the R3/R4 pair, two post-mitotic cells that are not specified by asymmetric cell division.
IPCO: Inference of Pathways from Co-variance analysis
Authors: Das Mrinmoy , Ghosh Tarini Shankar , Jeffery Ian B.
Published: June 2019

Key aspects of microbiome research are accurate identification of taxa followed by the profiling of their functionality. Amplicon profiling based on the 16S ribosomal DNA sequence is a ubiquitous technique to identify and profile the abundances of the various taxa. However, it does not provide information on their encoded functionality. Predictive tools which can accurately extrapolate the functional information of a microbiome based on taxonomic profile composition is essential. At present the applicability of these tools is however limited due to requirement of reference genomes from known species. We present IPCO (Inference of Pathways from Co-variance analysis), a new method of inferring functionality for 16S-based microbiome profiles independent of reference genomes. IPCO utilises the biological co-variance observed between paired taxonomic and functional profiles and co-varies it with the queried dataset. It outperforms other established methods both in terms of sample and feature profile prediction. Validation results confirmed that IPCO can replicate observed biological signals seen within shotgun and metabolite profiles. Comparative analysis of predicted functionality profiles with other popular 16S-based functional prediction tools indicates significantly lower performance with predicted functionality showing little to no correlation with paired shotgun features across samples. IPCO is implemented in R and available fromhttps://github.com/IPCO-Rlibrary/IPCO.
Survival of prey growing through gape-limited and apex predators
Authors: Anderson James J.
Published: June 2019

A mechanistic model based on first principles of growth and predator-prey behavior introduces the effects of a predator size distribution on the survival of rapidly growing prey. The model, fit to Chinook salmon data, can explain the observed increase in ocean survival with smolt ocean entrance length using different predator size-frequency distributions. The model introduces new dimensions to theories on predator-prey interactions and population recruitment and suggests the possibility that fish recruitment control can be highly variable; sometimes dominated by juvenile growth and encounters with gape-limited predators and other times dominated by adult encounters with apex predators. Additionally, a sensitivity analysis suggests that scale and otolith circuli spacing are insensitive indicators of size-selective mortality but the profile of adult survival with juvenile length provides information on the balance of size-dependent and size-independent mortality processes.
Mouse CHD4-NURD is required for neonatal spermatogonia survival and normal gonad development
Authors: de Castro Rodrigo O. , Previato Luciana , Carbajal Agustin , Goitea Victor , Griffin Courtney T. , Pezza Roberto J.
Published: June 2019

Testis development and sustained germ cell production in adults rely on the establishment and maintenance of spermatogonia stem cells and their proper differentiation into spermatocytes. Chromatin remodeling complexes regulate critical processes during gamete development by restricting or promoting accessibility of DNA repair and gene expression machineries to the chromatin. Here, we investigated the role of CHD4 and CHD3 catalytic subunits of the NURD complex during spermatogenesis. Germ cell-specific deletion of Chd4 early in gametogenesis, but not Chd3, resulted in arrested early gamete development due to failed cell survival of neonate undifferentiated spermatogonia stem cell population. Candidate assessment revealed that CHD4 controls expression of Dmrt1 and its downstream target Plzf, both described as prominent regulators of spermatogonia stem cell maintenance. Our results show the requirement of CHD4 in mammalian gametogenesis pointing to functions in gene expression early in the process.
Relationship between quinolone use and resistance of Staphylococcus epidermidis in patients with acne vulgaris
Authors: Nakase Keisuke , Yoshida Aoi , Saita Hikaru , Hayashi Nobukazu , Nishijima Setsuko , Nakaminami Hidemasa , Noguchi Norihisa
Published: June 2019

Staphylococcus epidermidis is a bacterium known to inhabit the skin. In treatment of acne vulgaris, the cutaneous milieu is exposed to oral or topical antimicrobials. We previously reported that the antimicrobial resistance of Cutibacterium acnes isolated from acne patients is affected by antimicrobial use. The aim of this study was to investigate the relationship between quinolone use and resistance in skin bacteria, particularly S. epidermidis, from acne patients. A total of 92 and 87 S. epidermidis strains isolated from clinic patients and hospital outpatients with acne vulgaris, respectively, were tested. No significant difference was found between the prevalence of methicillin‐resistant S. epidermidis (MRSE) strains from clinic patients (37.0%) and hospital outpatients (39.1%). The MRSE strains (20.6%, 14/68 strains) showed a significantly higher ratio of high‐level levofloxacin resistance (minimum inhibitory concentrations were 64 to ≥256 μg/mL) compared with methicillin‐susceptible S. epidermidis strains (2.7%, 3/111 strains) (P < 0.01). The rate of levofloxacin resistance in C. acnes strains, which were isolated from the same samples of acne patients, showed a strong positive correlation with that in S. epidermidis strains (r = 0.93, P < 0.01). The high‐level levofloxacin‐resistant strains were frequently found in patients with history of quinolone use compared with those without (P < 0.01). Our data showed for the first time that antimicrobial administration for acne treatment affects the antimicrobial resistance in not only C. acnes but also S. epidermidis. Thus, caution should be exercised in antimicrobial use for acne treatment to prevent increasing antimicrobial resistance in these species.
Shade tolerance and mycorrhizal type may influence sapling susceptibility to conspecific negative density dependence
Authors: Brown Alissa J. , Payne Christopher J. , White Peter S. , Peet Robert K.
Published: June 2019

The maintenance of tree diversity has been explained by multiple mechanisms. One of the most thoroughly studied is conspecific negative density dependence, in which specialist plant enemies reduce survivorship of seeds, seedlings or saplings located near adult conspecifics. Although there is much support that conspecific negative density dependence occurs in temperate forests, only a subset of the species investigated thus far exhibit this recruitment pattern. It remains unclear what drives differential susceptibility to conspecifics among tree species. Previous investigators have considered shade tolerance and mycorrhizal type (arbuscular mycorrhizal vs. ectomycorrhizal association) as two traits that might explain differential susceptibility to conspecific negative density dependence.

Here, we test whether these two plant traits predict susceptibility of tree saplings to conspecific negative density dependence in a temperate hardwood forest using three responses: spatial point patterns of saplings, sapling growth and sapling survival.

Spatial patterns of saplings indicate that shade tolerant species are less sensitive to conspecifics than shade intolerant species, but show no differences based on mycorrhizal type. Conversely, shade tolerant saplings exhibit reduced growth, but not survival, when located in areas with high conspecific density. We interpret this finding in light of the conservative functional strategies of shade tolerant species, which typically have low leaf nitrogen levels and slower growth to divert resources to tissue defence against enemies. We found an effect of mycorrhizal type interacting with adult conspecific density, where arbuscular mycorrhizal species show a greater reduction in growth than ectomycorrhizal species in areas dense with conspecifics.

Synthesis. We conclude that the shade tolerance level and the mycorrhizal type of temperate forest saplings may influence how their growth and survival respond to the adult conspecific trees in their neighbourhoods.
Political Uncertainty and Cost Stickiness: Evidence from National Elections around the World
Authors: Lee Woo‐Jong , Pittman Jeffrey , Saffar Walid
Published: June 2019

By analyzing a large panel of elections in 55 countries, we show that political uncertainty surrounding elections can affect asymmetric cost responses to activity changes (i.e., cost stickiness). In comparison to non‐election years, we find that the asymmetry in cost behaviors is stronger during election years in regressions that control for other firm‐level and country‐level determinants. In another series of tests, we report strong, robust evidence supporting the predictions that the importance of political uncertainty to cost stickiness is concentrated in countries with sound political and legal institutions. Collectively, the results imply that managers retain slack resources when political uncertainty is high but to be resolved soon.
Mental disorders and long‐term labour market outcomes: nationwide cohort study of 2 055 720 individuals
Authors: Hakulinen C. , Elovainio M. , Arffman M. , Lumme S. , Pirkola S. , Keskimäki I. , Manderbacka K. , Böckerman P.
Published: June 2019

Objective

To examine the associations between an onset of serious mental disorders before the age of 25 with subsequent employment, income and education outcomes.

Methods

Nationwide cohort study including individuals (n = 2 055 720) living in Finland between 1988–2015, who were alive at the end of the year they turned 25. Mental disorder diagnosis between ages 15 and 25 was used as the exposure. The level of education, employment status, annual wage or self‐employment earnings, and annual total income between ages 25 and 52 (measurement years 1988–2015) were used as the outcomes.

Results

All serious mental disorders were associated with increased risk of not being employed and not having any secondary or higher education between ages 25 and 52. The earnings for individuals with serious mental disorders were considerably low, and the annual median total income remained rather stable between ages 25 and 52 for most of the mental disorder groups.

Conclusions

Serious mental disorders are associated with low employment rates and poor educational outcomes, leading to a substantial loss of total earnings over the life course.
Course syllabi in GIS programming: Trends and patterns in the integration of computer science and programming
Authors: Bowlick Forrest J. , Bednarz Sarah W. , Goldberg Daniel W.
Published: June 2019

Understanding of fundamentals of computer science and abilities in programming are becoming more important components of the GIS practitioner's skillset. As the frontiers of GIS expand into areas of inquiry and modes of operation which require such domain capabilities, teaching and instruction in GIS must begin that shift as well. And while the knowledge, skills, and practices of the GIS practitioner have always been in flux, the range of potential topics from computer science and programming to integrate into GIS instruction is a major pedagogical challenge. This paper examines a range of syllabi from variant GIS programming courses to explore the landscape of programming coursework. Through content analysis, these syllabi reveal three general themes: courses built on learning scripting with Python, courses built on learning fundamentals of WebGIS, and courses built on learning fundamentals in geodatabase design and management. While each of these focus areas are impactful skills for GIS learners to explore, there is by no means any consistency or cohesion in how GIS programming courses operate, nor does there seem to be any general resources or approaches to unify course design. More work is necessary among GIS instructors to begin building evidence‐based practices in GIS programming instruction.
Establishment of a novel experimental model for muscle‐invasive bladder cancer using a dog bladder cancer organoid culture
Authors: Elbadawy Mohamed , Usui Tatsuya , Mori Takashi , Tsunedomi Ryouichi , Hazama Shoichi , Nabeta Rina , Uchide Tsuyoshi , Fukushima Ryuji , Yoshida Toshinori , Shibutani Makoto , Tanaka Takaharu , Masuda Sosuke , Okada Rena , Ichikawa Ryo , Omatsu Tsutomu , Mizutani Tetsuya , Katayama Yukie , Noguchi Shunsuke , Iwai Satomi , Nakagawa Takayuki , Shinohara Yuta , Kaneda Masahiro , Yamawaki Hideyuki , Sasaki Kazuaki
Published: June 2019

In human and dogs, bladder cancer (BC) is the most common neoplasm affecting the urinary tract. Dog BC resembles human muscle‐invasive BC in histopathological characteristics and gene expression profiles, and could be an important research model for this disease. Cancer patient‐derived organoid culture can recapitulate organ structures and maintains the gene expression profiles of original tumor tissues. In a previous study, we generated dog prostate cancer organoids using urine samples, however dog BC organoids had never been produced. Therefore we aimed to generate dog BC organoids using urine samples and check their histopathological characteristics, drug sensitivity, and gene expression profiles. Organoids from individual BC dogs were successfully generated, expressed urothelial cell markers (CK7, CK20, and UPK3A) and exhibited tumorigenesis in vivo. In a cell viability assay, the response to combined treatment with a range of anticancer drugs (cisplatin, vinblastine, gemcitabine or piroxicam) was markedly different in each BC organoid. In RNA‐sequencing analysis, expression levels of basal cell markers (CK5 and DSG3) and several novel genes (MMP28, CTSE, CNN3, TFPI2, COL17A1, and AGPAT4) were upregulated in BC organoids compared with normal bladder tissues or two‐dimensional (2D) BC cell lines. These established dog BC organoids might be a useful tool, not only to determine suitable chemotherapy for BC diseased dogs but also to identify novel biomarkers in human muscle‐invasive BC. In the present study, for the 1st time, dog BC organoids were generated and several specifically upregulated organoid genes were identified. Our data suggest that dog BC organoids might become a new tool to provide fresh insights into both dog BC therapy and diagnostic biomarkers.