bluuebunny/crossref_metadata_2025 huggingface dataset:
Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig
Authors: Kong Qingran , Yang Xu , Zhang Heng , Liu Shichao , Zhao Jianchao , Zhang Jiaming , Weng Xiaogang , Jin Junxue , Liu Zhonghua
Published: November 2019

The inner cell mass (ICM) in blastocyst is the origin of all somatic and germ cells in mammals and pluripotent stem cells (PSCs) in vitro. As the conserved principles between pig and human, here we performed comprehensive single‐cell RNA‐seq for porcine early embryos from oocyte to early blastocyst (EB). We show the specification of the ICM and trophectoderm in morula and the molecular signature of the precursors. We demonstrate the existence of naïve pluripotency signature in morula and ICM of EB, and the specific pluripotent genes and the activity of signalling pathways highlight the characteristics of the naïve pluripotency. We observe the absence of dosage compensation with respect to X‐chromosome (XC) in morula, and incomplete dosage compensation in the EB. However, the dynamics of dosage compensation may be independent of the expression of XIST induced XC inactivation. Our study describes molecular landmarks of embryogenesis in pig that will provide a better strategy for derivation of porcine PSCs and improve research in regenerative medicine.
Auxiliary subunits control biophysical properties and response to compound NS5806 of the Kv4 potassium channel complex
Authors: Zhang Hongxue , Zhang Hua , Wang Chanjuan , Wang Yuhong , Zou Ruya , Shi Chenxia , Guan Bingcai , Gamper Nikita , Xu Yanfang
Published: November 2019

Kv4 pore‐forming subunits co‐assemble with β‐subunits including KChIP2 and DPP6 and the resultant complexes conduct cardiac transient outward K+ current (Ito). Compound NS5806 has been shown to potentate Ito in canine cardiomyocytes; however, its effects on Ito in other species yet to be determined. We found that NS5806 inhibited native Ito in a concentration‐dependent manner (0.1~30 μM) in both mouse ventricular cardiomyocytes and human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs), but potentiated Ito in the canine cardiomyocytes. In HEK293 cells co‐transfected with cloned Kv4.3 (or Kv4.2) and β‐subunit KChIP2, NS5806 significantly increased the peak current amplitude and slowed the inactivation. In contrast, NS5806 suppressed the current and accelerated inactivation of the channels when cells were co‐transfected with Kv4.3 (or Kv4.2), KChIP2 and another β‐subunit, DPP6‐L (long isoform). Western blot analysis showed that DPP6‐L was dominantly expressed in both mouse ventricular myocardium and hiPSC‐CMs, while it was almost undetectable in canine ventricular myocardium. In addition, low level of DPP6‐S expression was found in canine heart, whereas levels of KChIP2 expression were comparable among all three species. siRNA knockdown of DPP6 antagonized the Ito inhibition by NS5806 in hiPSC‐CMs. Molecular docking simulation suggested that DPP6‐L may associate with KChIP2 subunits. Mutations of putative KChIP2‐interacting residues of DPP6‐L reversed the inhibitory effect of NS5806 into potentiation of the current. We conclude that a pharmacological modulator can elicit opposite regulatory effects on Kv4 channel complex among different species, depending on the presence of distinct β‐subunits. These findings provide novel insight into the molecular design and regulation of cardiac Ito. Since Ito is a potential therapeutic target for treatment of multiple cardiovascular diseases, our data will facilitate the development of new therapeutic Ito modulators.
Alan William Cuthbert. 7 May 1932—27 August 2016
Authors: Edwardson J. Michael
Published: November 2019

Alan Cuthbert carried out ground-breaking work on epithelial ion transport. He used radiolabelled amiloride and benzamil to measure the sodium channel density in epithelia from frog skin and toad bladder, tissues that are good models for the distal section of the mammalian kidney tubule. This work shed important new light on how the properties of these channels are modified by hormones such as aldosterone and antidiuretic hormone, and increased our understanding of how diuretics affect kidney function. Later, he focused on the ion transport deficits that underlie cystic fibrosis (CF), and was a member of the team that showed that the ion transport defect could be corrected in CF transgenic mice by gene therapy. Alan was Sheild Professor of Pharmacology and Head of the Department of Pharmacology at the University of Cambridge from 1979 until his retirement in 1999. During this time he was instrumental in moving the Department from the Addenbrooke's Hospital site to a new building in the centre of town. He was also Master of Fitzwilliam College from 1991 until 1999. Alan made major contributions to pharmacology nationally and internationally, serving as chairman of the editorial board of the
British Journal of Pharmacology
for eight years, and as President of the Federation of European Pharmacological Societies for two years. In recognition of his contributions to the subject, the British Pharmacological Society awarded him their Wellcome Gold Medal in 2005. After his retirement, he continued his research in the Department of Medicine, pursuing novel pharmacological approaches to the treatment of CF.
Tomography of scaling
Authors: Barthelemy Marc
Published: November 2019

Scaling describes how a given quantity
Y
that characterizes a system varies with its size
P
. For most complex systems, it is of the form

Y
∼

P

β

with a non-trivial value of the exponent
β
, usually determined by regression methods. The presence of noise can make it difficult to conclude about the existence of a nonlinear behaviour with
β
≠ 1 and we propose here to circumvent fitting problems by investigating how two different systems of sizes
P
1
and
P
2
are related to each other. This leads us to define a local scaling exponent
β
loc
that we study versus the ratio
P
2
/
P
1
and provides some sort of ‘tomography scan’ of scaling across different values of the size ratio, allowing us to assess the relevance of nonlinearity in the system and to identify an effective exponent that minimizes the error for predicting the value of
Y
. We illustrate this method on various real-world datasets for cities and show that our method reinforces in some cases the standard analysis, but is also able to provide new insights in inconclusive cases and to detect problems in the scaling form such as the absence of a single scaling exponent or the presence of threshold effects.
Heat conduction in porcine muscle and blood: experiments and time-fractional telegraph equation model
Authors: Madhukar Amit , Park Yeonsoo , Kim Woojae , Sunaryanto Hans Julian , Berlin Richard , Chamorro Leonardo P. , Bentsman Joseph , Ostoja-Starzewski Martin
Published: November 2019

This paper presents experimental evidence for the damped-hyperbolic nature of transient heat conduction in porcine muscle tissue and blood. An examination of integer order and Maxwell–Cattaneo heat conduction models indicates that the latter, in effect resulting in a time-fractional telegraph (TFT) equation, provides the best fit to transient heat phenomena in such materials. The numerical method is verified on Dirichlet and Neumann initial boundary value problems using existing analytical results. Overall, the TFT equation captures the wave-like nature of heat conduction and temperature profiles obtained in experiments, while reducing the need for further tunable parameters.
Loss of CRMP2 O-GlcNAcylation leads to reduced novel object recognition performance in mice
Authors: Muha Villo , Williamson Ritchie , Hills Rachel , McNeilly Alison D. , McWilliams Thomas G. , Alonso Jana , Schimpl Marianne , Leney Aneika C. , Heck Albert J. R. , Sutherland Calum , Read Kevin D. , McCrimmon Rory J. , Brooks Simon P. , van Aalten Daan M. F.
Published: November 2019

O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, the mechanistic links between these phenotypes and site-specific O-GlcNAcylation remain largely unexplored. Here, we show that Ser517 O-GlcNAcylation of the microtubule-binding protein Collapsin Response Mediator Protein-2 (CRMP2) increases with age. By generating and characterizing a

Crmp2
S517A

knock-in mouse model, we demonstrate that loss of O-GlcNAcylation leads to a small decrease in body weight and mild memory impairment, suggesting that Ser517 O-GlcNAcylation has a small but detectable impact on mouse physiology and cognitive function.
Limiting stochastic processes of shift-periodic dynamical systems
Authors: Stadlmann Julia , Erban Radek
Published: November 2019

A shift-periodic map is a one-dimensional map from the real line to itself which is periodic up to a linear translation and allowed to have singularities. It is shown that iterative sequences
x

n
+1

=
F
(
x

n

) generated by such maps display rich dynamical behaviour. The integer parts

⌊

x

n

⌋

give a discrete-time random walk for a suitable initial distribution of
x
0
and converge in certain limits to Brownian motion or more general Lévy processes. Furthermore, for certain shift-periodic maps with small holes on [0,1], convergence of trajectories to a continuous-time random walk is shown in a limit.
Boundary-polarized subsonic Rayleigh waves under conditions of semi-simple Stroh degeneracy
Authors: Barnett D. M.
Published: November 2019

We undertake a study of subsonic free surface (Rayleigh) waves in linear elastic half-spaces of general anisotropy
when the wave polarization vector lies in the half-space boundary
, if and when the formalism due to A. N. Stroh exhibits semi-simple degeneracy at the Rayleigh speed

v
R

. It is shown that the class of subsonic steady wave motions at any subsonic velocity exhibiting semi-simple degeneracy includes a free surface wave whenever the first transonic state is not exceptional, in accordance with general surface wave theory. Furthermore, such a free surface wave is always necessarily
boundary-polarized
! In general, the restrictions on the half-space elastic constants permitting the existence of semi-simplicity in steady motion at a subsonic phase speed are not satisfied in any physically realized medium which is elastically stable, but we outline an algorithm which allows one to construct the elastic stiffnesses of media which exist mathematically and allow for the existence of subsonic free surface waves (which are necessarily boundary-polarized) under conditions of semi-simple degeneracy in the sense of Stroh's formalism.
Divergent evolutionary morphology of the axial skeleton as a potential key innovation in modern cetaceans
Authors: Gillet Amandine , Frédérich Bruno , Parmentier Eric
Published: November 2019

Cetaceans represent the most diverse clade of extant marine tetrapods. Although the restructuring of oceans could have contributed to their diversity, other factors might also be involved. Similar to ichthyosaurs and sharks, variation of morphological traits could have promoted the colonization of new ecological niches and supported their diversification. By combining morphological data describing the axial skeleton of 73 cetacean species with phylogenetic comparative methods, we demonstrate that the vertebral morphology of cetaceans is associated with their habitat. All riverine and coastal species possess a small body size, lengthened vertebrae and a low vertebral count compared with open ocean species. Extant cetaceans have followed two distinct evolutionary pathways relative to their ecology. Whereas most offshore species such as baleen whales evolved towards an increased body size while retaining a low vertebral count, small oceanic dolphins underwent deep modifications of their axial skeleton with an extremely high number of short vertebrae. Our comparative analyses provide evidence these vertebral modifications have potentially operated as key innovations. These novelties contributed to their explosive radiation, resulting in an efficient swimming style that provides energetic advantages to small-sized species.
Exceptional preservation of comma shrimp from a mid-Cretaceous Lagerstätte of Colombia, and the origins of crown Cumacea
Authors: Luque Javier , Gerken Sarah
Published: November 2019

Mesozoic rocks with exceptional preservation of marine arthropods are known worldwide but largely restricted to mid–high latitudes. The scarcity of assemblages with exceptional preservation in low, tropical latitudes greatly limits our understanding of the origins of several modern groups and the evolution of tropical biotas through time. Here, we report the oldest crown Cumacea, or ‘comma’ shrimp (Arthropoda: Eumalacostraca: Peracarida) with modern familial affinities, from a new mid-Cretaceous (95–90 Ma) Lagerstätte in tropical South America. Cumaceans have one of the poorest fossil records among marine arthropods, despite today being abundant and speciose benthic organisms associated with fine-grained sediments with high fossilization potential.Eobodotria muiscagen. et sp. nov., found in mass accumulation surfaces, preserves with detail the gut, mouth parts, thoracic legs/pereopods, pleopods, uropods bearing setae, antennal flagella and even small eyes bearing ommatidia. These features, rarely preserved in fossil crustaceans, plus the large sample size (greater than 200 individuals, 6–8 mm long), allow us to discuss phylogenetic/systematic aspects and explore possible mechanisms behind their unusual accumulation.Eobodotriabridges an approximately 165 Myr gap in the cumacean fossil record, provides a reliable calibration point for phylogenetic studies and expands our understanding of exceptional preservation in past and present tropical settings.
Specialized sledge dogs accompanied Inuit dispersal across the North American Arctic
Authors: Ameen Carly , Feuerborn Tatiana R. , Brown Sarah K. , Linderholm Anna , Hulme-Beaman Ardern , Lebrasseur Ophélie , Sinding Mikkel-Holger S. , Lounsberry Zachary T. , Lin Audrey T. , Appelt Martin , Bachmann Lutz , Betts Matthew , Britton Kate , Darwent John , Dietz Rune , Fredholm Merete , Gopalakrishnan Shyam , Goriunova Olga I. , Grønnow Bjarne , Haile James , Hallsson Jón Hallsteinn , Harrison Ramona , Heide-Jørgensen Mads Peter , Knecht Rick , Losey Robert J. , Masson-MacLean Edouard , McGovern Thomas H. , McManus-Fry Ellen , Meldgaard Morten , Midtdal Åslaug , Moss Madonna L. , Nikitin Iurii G. , Nomokonova Tatiana , Pálsdóttir Albína Hulda , Perri Angela , Popov Aleksandr N. , Rankin Lisa , Reuther Joshua D. , Sablin Mikhail , Schmidt Anne Lisbeth , Shirar Scott , Smiarowski Konrad , Sonne Christian , Stiner Mary C. , Vasyukov Mitya , West Catherine F. , Ween Gro Birgit , Wennerberg Sanne Eline , Wiig Øystein , Woollett James , Dalén Love , Hansen Anders J. , P. Gilbert M. Thomas , Sacks Benjamin N. , Frantz Laurent , Larson Greger , Dobney Keith , Darwent Christyann M. , Evin Allowen
Published: November 2019

Domestic dogs have been central to life in the North American Arctic for millennia. The ancestors of the Inuit were the first to introduce the widespread usage of dog sledge transportation technology to the Americas, but whether the Inuit adopted local Palaeo-Inuit dogs or introduced a new dog population to the region remains unknown. To test these hypotheses, we generated mitochondrial DNA and geometric morphometric data of skull and dental elements from a total of 922 North American Arctic dogs and wolves spanning over 4500 years. Our analyses revealed that dogs from Inuit sites dating from 2000 BP possess morphological and genetic signatures that distinguish them from earlier Palaeo-Inuit dogs, and identified a novel mitochondrial clade in eastern Siberia and Alaska. The genetic legacy of these Inuit dogs survives today in modern Arctic sledge dogs despite phenotypic differences between archaeological and modern Arctic dogs. Together, our data reveal that Inuit dogs derive from a secondary pre-contact migration of dogs distinct from Palaeo-Inuit dogs, and probably aided the Inuit expansion across the North American Arctic beginning around 1000 BP.
Small population size and low genomic diversity have no effect on fitness in experimental translocations of a wild fish
Authors: Yates M. C. , Bowles E. , Fraser D. J.
Published: November 2019

Little empirical work in nature has quantified how wild populations with varying effective population sizes and genetic diversity perform when exposed to a gradient of ecologically important environmental conditions. To achieve this, juvenile brook trout from 12 isolated populations or closed metapopulations that differ substantially in population size and genetic diversity were transplanted to previously fishless ponds spanning a wide gradient of ecologically important variables. We evaluated the effect of genome-wide variation, effective population size (
N
e
), pond habitat, and initial body size on two fitness correlates (survival and growth). Genetic variables had no effect on either fitness correlate, which was determined primarily by habitat (pond temperature, depth, and pH) and initial body size. These results suggest that some vertebrate populations with low genomic diversity, low
N
e
, and long-term isolation can represent important sources of variation and are capable of maintaining fitness in, and ultimately persisting and adapting to, changing environments. Our results also reinforce the paramount importance of improving available habitat and slowing habitat degradation for species conservation.
Patterns of self-medication among university students in San Jose, Costa Rica
Authors: Norori Maria Natalia
Published: November 2019

Background

Self-medication is defined as the use of drugs to treat self-diagnosed symptoms without the supervision of healthcare physicians. Self-medication is a growing public health phenomenon and is associated with risks such as misdiagnosis and drug toxicity. This study aimed to identify the patterns associated with the practice of self- medication among university students in San José, Costa Rica.

Methods

A descriptive cross-sectional study was designed and conducted to identify variables associated. Information was collected on the conditions treated, medications used and their sources.

Results

The study found that self-medication is highly prevalent among Costa Rican university students. 91.4% of the sample reported self-medicating, with each student consuming an average of 2.15, ± 1,08 drugs. The most Frequently used active ingredients were paracetamol and Ibuprofen. Results also show a relation between the most consumed types of drugs and the principal causes of drug intoxication reported by Costa Rica’s National Poison Center. 77.8% of the participants considered self-medication a risky practice.

Conclusions

Self-medication is common among Costa Rican university students. The prevalence found is higher than that reported in previous studies conducted in the country. These findings suggest the need to implement prevention campaigns and regulatory policies to ensure the safe consumption of medical drugs.
Algorithmic discovery of dynamic models from infectious disease data
Authors: Horrocks Jonathan , Bauch Chris T.
Published: November 2019

Theoretical models are typically developed through a deductive process where a researcher formulates a system of dynamic equations from hypothesized mechanisms. Recent advances in algorithmic methods can discover dynamic models inductively– directly from data. Most previous research has tested these methods by rediscovering models from synthetic data generated by the already known model. Here we apply Sparse Identification of Nonlinear Dynamics (SINDy) to discover mechanistic equations for disease dynamics from case notification data for measles, chickenpox, and rubella. The discovered models provide a good qualitative fit to the observed dynamics for all three diseases, However, the SINDy chickenpox model appears to overfit the empirical data, and recovering qualitatively correct rubella dynamics requires using power spectral density in the goodness-of-fit criterion. When SINDy uses a library of second-order functions, the discovered models tend to include mass action incidence and a seasonally varying transmission rate–a common feature of existing epidemiological models for childhood infectious diseases. We also find that the SINDy measles model is capable of out-of-sample prediction of a dynamical regime shift in measles case notification data. These results demonstrate the potential for algorithmic model discovery to enrich scientific understanding by providing a complementary approach to developing theoretical models.
Estimating the Per-Application Effectiveness of Chlorhexidine Gluconate and Mupirocin in Methicillin-resistant Staphylococcus aureus Decolonization in Intensive Care Units
Authors: Lofgren Eric T. , Mietchen Matthew , Short Christopher , Dicks Kristen V. , Moehring Rebekah , Anderson Deverick ,   for the CDC MIND-Healthcare Program
Published: November 2019

Introduction

Chlorhexidine gluconate and mupirocin are widely used to decolonize patients with methicillin-resistant Staphylococcus aureus (MRSA) and reduce risks of infection in hospitalized populations. The probability that a treated patient would be decolonized, which we term per-application effectiveness, is difficult to directly measure. Quantifying the efficacy of per-application effectiveness of CHG and mupirocin is important for studies evaluating alternative decolonization strategies or schedules as well as identifying whether there is room for improved decolonizing agents.

Methods

Using a stochastic compartmental model of an intensive care unit (ICU), the per-application effectiveness of chlorhexidine and mupirocin were estimated using approximate Bayesian computation. Extended sensitivity analysis examined the potential impact of a latent period between MRSA colonization and detection, the timing of decolonization administration, and parameter uncertainty.

Results

The estimated per-application effectiveness of chlorhexidine was 0.15 (95% Credible Interval: 0.01, 0.42), while the estimated effectiveness of mupirocin was is 0.15 (95% CI: 0.01, 0.54). A lag in colonization detection markedly reduced both estimates, which were particularly sensitive to the value to the modeled contact rate between nurses and patients. Gaps longer than 24-hours in the administration of decolonizing agents still resulted in substantial reduction of within-ICU MRSA transmission.

Discussion

The per-application effectiveness estimates for chlorhexidine and mupirocin suggest there is room for substantial improvement in anti-MRSA disinfectants, either in the compounds themselves, or in their delivery mechanism. Despite these estimates, these agents are robust to delays in administration, which may help in alleviating concerns over patient comfort or toxicity.
A Cognitive Development Chart for School-age Children and Adolescents
Authors: Simioni André R. , Pine Daniel S. , Sato João R. , Pan Pedro M. , Fonseca Rochele Paz , Schafer Julia , Miguel Euripedes C. , Mari Jair J. , Gadelha Ary , Bressan Rodrigo A. , Rohde Luis A. , Salum Giovanni A.
Published: November 2019

Objective

To evaluate the reliability and predictive utility of a time-efficient cognitive development chart that seeks to identify children and adolescents with high-risk for multiple outcomes such as mental health problems, substance use, and educational difficulties.

Method

We analyzed data from the Brazilian High-Risk Cohort for Psychiatric Disorders (HRC), a longitudinal school-based study conducted from 2010-2011 to 2013-2014. Participants were 2,239 children and adolescents, 6 to 17 years of age, who completed the cognitive assessment at baseline. The task used to track cognitive development was the Two Choice Reaction Time task (<3 minutes of duration, computer-based), which assesses the accuracy and speed of perceptual decision-making. Mental health, substance use, and educational outcomes were assessed by validated standardized methods. Key variables were measured at baseline and 3-year follow-up. The predictive utility was assessed using static (deviations from the age-expected performance at baseline) and dynamic (deviations from the age-expected change in performance over time) indicators.

Results

The reliability of the task parameter was high (intra-class correlation coefficient = 0.8). Static indicators of cognitive development significantly predicted concurrent mental, intellectual and educational difficulties, as well as incident and persistent educational difficulties and substance use in the 3-year follow-up. Dynamic indicators predicted persistent mental health problems.

Conclusion

Primary-care and mental health professionals need a time-efficient tool for tracking deviations from age-expected cognitive development, which predicts multiple unwanted outcomes at the same time. If replicated, future results could support the generation of tools for tracking risk for mental health, substance use, and educational difficulties.
Electrophysiological Studies of Reception of Facial Communication in Autism Spectrum Disorder and Schizophrenia
Authors: Levy Emily J. , Foss-Feig Jennifer , Isenstein Emily L. , Srihari Vinod , Anticevic Alan , Naples Adam J. , McPartland James C.
Published: November 2019

Autism spectrum disorder (ASD) and schizophrenia spectrum disorders (SZ) are both characterized by difficulty with social cognition. Likewise, social brain activity is atypical in both disorders and indicates atypical reception of facial communication – a key area in the Research Domain Criteria framework for identifying common biological underpinnings of psychiatric disorders. To identify areas of overlap and dissociation between ASD and SZ, this paper reviews studies of electrophysiological (EEG) response to facial stimuli across ASD and SZ populations. We focus on findings regarding amplitude and latency of four brain responses implicated in social perception: P100, N170, N250, and P300. There were many inconsistent findings in both the ASD and SZ literatures; however, replication across studies was strongest for delayed N170 latency in ASD and attenuated N170 amplitude in SZ. EEG responses corresponded with clinical symptoms in multiple samples. These results highlight the challenges associated with replicating research findings in heterogeneous clinical populations, as well as the need for transdiagnostic research and for designing studies to examine relationships among continuous quantifications of behavior and neural activity across neurodevelopmental disorders.
Single-cell tumor phylogeny inference with copy-number constrained mutation losses
Authors: Satas Gryte , Zaccaria Simone , Mon Geoffrey , Raphael Benjamin J.
Published: November 2019

Motivation

Single-cell DNA sequencing enables the measurement of somatic mutations in individual tumor cells, and provides data to reconstruct the evolutionary history of the tumor. Nearly all existing methods to construct phylogenetic trees from single-cell sequencing data use single-nucleotide variants (SNVs) as markers. However, most solid tumors contain copy-number aberrations (CNAs) which can overlap loci containing SNVs. Particularly problematic are CNAs that delete an SNV, thus returning the SNV locus to the unmutated state. Such mutation losses are allowed in some models of SNV evolution, but these models are generally too permissive, allowing mutation losses without evidence of a CNA overlapping the locus.

Results

We introduce a novel loss-supported evolutionary model, a generalization of the infinite sites and Dollo models, that constrains mutation losses to loci with evidence of a decrease in copy number. We design a new algorithm, Single-Cell Algorithm for Reconstructing the Loss-supported Evolution of Tumors (Scarlet), that infers phylogenies from single-cell tumor sequencing data using the loss-supported model and a probabilistic model of sequencing errors and allele dropout. On simulated data, we show that Scarlet outperforms current single-cell phylogeny methods, recovering more accurate trees and correcting errors in SNV data. On single-cell sequencing data from a metastatic colorectal cancer patient, Scarlet constructs a phylogeny that is both more consistent with the observed copy-number data and also reveals a simpler monooclonal seeding of the metastasis, contrasting with published reports of polyclonal seeding in this patient. Scarlet substantially improves single-cell phylogeny inference in tumors with CNAs, yielding new insights into the analysis of tumor evolution.

Availability

Software is available at github.com/raphael-group/scarlet

Contact

braphael@princeton.edu
Independence of HIF1a and androgen signaling pathways in prostate cancer
Authors: Tran Maxine GB , Bibby Becky AS , Yang Lingjian , Lo Franklin , Warren Anne , Shukla Deepa , Osborne Michelle , Hadfield James , Carroll Thomas , Stark Rory , Scott Helen , Ramos-Montoya Antonio , Massie Charlie , Maxwell Patrick , West Catharine ML , Mills Ian G. , Neal David E.
Published: November 2019

Androgen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.
Tensor Image Registration Library: Automated Non-Linear Registration of Sparsely Sampled Histological Specimens to Post-Mortem MRI of the Whole Human Brain
Authors: Huszar Istvan N. , Pallebage-Gamarallage Menuka , Foxley Sean , Tendler Benjamin C. , Leonte Anna , Hiemstra Marlies , Mollink Jeroen , Smart Adele , Bangerter-Christensen Sarah , Brooks Hannah , Turner Martin R. , Ansorge Olaf , Miller Karla L. , Jenkinson Mark
Published: November 2019

There is a need to understand the histopathological basis of MRI signal characteristics in complex biological matter. Microstructural imaging holds promise for sensitive and specific indicators of the early stages of human neurodegeneration but requires validation against traditional histological markers before it can be reliably applied in the clinical setting. Validation relies on a precise and preferably automatic method to align MRI and histological images of the same tissue, which poses unique challenges compared to more conventional MRI-to-MRI registration.

A customisable open-source platform, Tensor Image Registration Library (TIRL) is presented. Based on TIRL, a fully automated pipeline was implemented to align small stained histological images with dissection photographs of corresponding tissue blocks and coronal brain slices, and further with high-resolution (0.5 mm) whole-brain post-mortem MRI data. The pipeline performed three separate deformable registrations to achieve accurate mapping between whole-brain MRI and small-slide histology coordinates. The robustness and accuracy of the individual registration steps were evaluated using both simulated data and real-life images from 6 different anatomical locations of one post-mortem human brain.

The automated registration method demonstrated sub-millimetre accuracy in all steps, robustness against tissue damage, and good reproducibility between experiments. The method also outperformed manual landmark-based slice-to-volume registration, also correcting for curvatures in the slicing plane. Due to the customisability of TIRL, the pipeline can be conveniently adapted for other research needs and is therefore suitable for the large-scale comparison of routinely collected histology and MRI data.

Highlights

TIRL: new framework for prototyping bespoke image registration pipelines

Pipeline for automated registration of small-slide histology to whole-brain MRI

Slice-to-volume registration accounting for through-plane deformations

No need for serial histological sampling
Functional channels in matureE. colicolonies
Authors: Rooney Liam M. , Amos William B. , Hoskisson Paul A. , McConnell Gail
Published: November 2019

Biofilms are important in medicine, industry and the natural environment, however their structure is largely unexplored across multiple spatial scales. We have studied the architecture of matureEscherichia colimacro-colony biofilms by means of the Mesolens, an optical system which uniquely allows simultaneous imaging of individual bacteria and over one hundred cubic millimetres of its biofilm milieu. Our chief finding is the presence of intra-colony channels on the order of 10 μm in diameter inE. colibiofilms. These channels have a characteristic structure and reform after total mechanical disaggregation of the colony. We present evidence that the channels transport particles and function to assist the absorption of nutrients. These channels potentially offer a new route for the delivery of dispersal agents or antimicrobial drugs to biofilms, ultimately lowering their impact on public health and industry.
Refining the transcriptome of the human malaria parasite Plasmodium falciparum using amplification-free RNA-seq
Authors: Chappell Lia , Ross Philipp , Orchard Lindsey , Otto Thomas D. , Berriman Matthew , Rayner Julian C. , Llinás Manuel
Published: November 2019

Plasmodium parasites undergo several major developmental transitions during their complex lifecycle, which are enabled by precisely ordered gene expression programs. Transcriptomes from the 48-hour blood stages of the major human malaria parasite Plasmodium falciparum have been described using cDNA microarrays and RNA-seq, but these assays have not always performed well within non-coding regions, where the AT-content is often 90-95%. We developed a directional, amplification-free RNA-seq protocol (DAFT-seq) to reduce bias against AT-rich cDNA, which we have applied to three strains of P. falciparum (3D7, HB3 and IT). While strain-specific differences were detected, overall there is strong conservation between the transcriptional profiles. For the 3D7 reference strain, transcription was detected from 89% of the genome, with over 75% of the genome transcribed into mRNAs. These datasets allowed us to refine the 5’ and 3’ untranslated regions (UTRs), which can be variable, long (>1,000 nt), and often overlap those of adjacent transcripts. We also find that transcription from bidirectional promoters frequently results in non-coding, antisense transcripts. By capturing the 5’ ends of mRNAs, we reveal both constant and dynamic use of transcriptional start sites across the intraerythrocytic developmental cycle resulting in an updated view of the P. falciparum transcriptome.
Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals
Authors: Poplimont Hugo , Georgantzoglou Antonios , Boulch Morgane , Coombs Caroline , Papaleonidopoulou Foteini , Sarris Milka
Published: November 2019

Neutrophils are major inflammatory cells that rapidly infiltrate injured tissues to provide antimicrobial functions. A key step in their response is the paracrine release of the attractant LTB4, which switches the migration mode from exploratory patrolling to coordinated swarming. This leads to dense clusters that may further disrupt tissue architecture. The coordination mechanism underpinning neutrophil swarms is elusive. Here we show that neutrophils swarms require mutual reinforcement of damage signalling at the wound core. New biosensors and live imaging in zebrafish revealed that neutrophil chemoattractant synthesis is triggered by a sustained calcium flux upon contact with necrotic tissue and sensing of the damage signal ATP. This ‘calcium alarm’ signal propagates in the nascent neutrophil cluster through connexin-43 hemichannels, which allow release of intracellular ATP. This enables rapid assembly of a centralised, supracellular chemoattractant source, which is instrumental for coordinated recruitment and maximal cell gathering.
Raw milk for human consumption may carry antimicrobial resistance genes
Authors: Gréta Tóth Adrienn , Csabai István , Krikó Eszter , Tőzsér Dóra , Maróti Gergely , Patai Árpád V. , Makrai László , Szita Géza , Solymosi Norbert
Published: November 2019

Background

The increasing prevalence of antimicrobial resistance (AMR) is a significant threat to global health. The widespread use of antibiotics is increasingly shortening the time it takes for resistant strains to develop. More and more multi-drug-resistant bacterial strains cause life-threatening infections and the death of tens of thousands of people each year. Beyond disease control animals are often given antibiotics for growth promotion or increased feed efficiency, which further increase the chance of the development of multi-resistant strains. After the consumption of unprocessed animal products, these strains may meet the human bacteriota. Among the foodborne and the human populations, antimicrobial resistance genes (ARGs) may be shared by horizontal gene transfer. This study aims to test the presence of antimicrobial resistance genes in milk metagenome, investigate their genetic position and their linkage to mobile genetic elements.

Results

We have analyzed raw milk samples from public markets sold for human consumption. The milk samples contained genetic material from various bacterial species and the detailed analysis uncovered the presence of several antimicrobial resistance genes. The samples contained complete ARGs influencing the effectiveness of acridine dye, cephalosporin, cephamycin, fluoroquinolone, penam, peptide antibiotics and tetracycline. One of the ARGs, PC1 beta-lactamase may also be a mobile element that facilitates the transfer of resistance genes to other bacteria, e.g. to the ones living in the human gut.

Conclusion

Besides the animal products’ antibiotic residuals, their potentially transmissible antimicrobial resistance gene content may also contribute to the development of human pathogenic bacteria’s antimicrobial resistance.
Heat production in a feeding matrix formed on carrion by communally breeding beetles
Authors: Matuszewski Szymon , Mądra-Bielewicz Anna
Published: November 2019

Insects regulate their body temperature mostly behaviourally, by changing posture or microhabitat. These strategies may be ineffective in some habitats, for example on carrion. Carrion beetles create a feeding matrix by applying to cadaver surface anal or oral exudates. We tested the hypothesis that the matrix, which is formed on carrion by communally breeding beetleNecrodes littoralisL. (Silphidae), produces heat that enhances insect fitness. Using thermal imaging we demonstrate that heat produced in the matrix formed on meat by adult or larval beetles is larger than in meat decomposing without insects. Larval beetles regularly warmed up in the matrix. Moreover, by comparing matrix temperature and larval fitness in colonies with and without preparation of meat by adult beetles, we provide evidence that formation of a matrix by adult beetles has deferred thermal effects for larval microhabitat. We found an increase in heat production of the matrix and a decrease in development time and mortality of larvae after adult beetles applied their exudates on meat in the pre-larval phase. Our findings indicate that spreading of exudates over carrion byNecrodeslarvae, apart from other likely functions (e.g. digesting carrion or promoting growth of beneficial microbes), facilitates thermoregulation. In case of adult beetles, this behaviour brings distinct thermal benefits for their offspring and therefore may be viewed as a new form of indirect parental care with an important thermal component.
Wounding and insect feeding trigger two independent MAPK pathways with distinct regulation and kinetics
Authors: Sözen Cécile , Schenk Sebastian T. , Boudsocq Marie , Chardin Camille , Almeida-Trapp Marilia , Krapp Anne , Hirt Heribert , Mithöfer Axel , Colcombet Jean
Published: November 2019

Wounding is caused by abiotic and biotic factors and triggers complex short- and long-term responses at the local and systemic level. These responses are under the control of complex signaling pathways, which are still poorly understood. Here, we show that the rapid activation of MKK4/5-MPK3/6 by wounding is independent of jasmonic acid (JA) signaling and that, contrary to what happens in tobacco, this fast module does not control wound-triggered JA accumulation in Arabidopsis. We also demonstrate that a second MAPK module, constituted by MKK3 and the clade-C MAPKs MPK1/2/7, is activated by wounding in an independent manner. We provide evidence that the activation of this MKK3-MPK1/2/7 module occurs mainly through wound-induced JA production via the transcriptional regulation of upstream clade-III MAP3Ks and particularly MAP3K14. We show that mkk3 mutant plants are more susceptible to the larvae of the generalist lepidopteran herbivore Spodoptera littoralis, indicating that the MKK3-MPK1/2/7 module is involved in counteracting insect feeding.

One sentence summary

Wounding induces the parallel activation of a rapid signaling module (MKK4/5-MPK3/6) and a JA-dependent slow one (MAP3K14-MKK3-MPK1/2/7/14) to restrict insect feeding.
STing: accurate and ultrafast genomic profiling with exact sequence matches
Authors: Espitia-Navarro Hector F. , Chande Aroon T. , Nagar Shashwat D. , Smith Heather , Jordan I. King , Rishishwar Lavanya
Published: November 2019

Genome-enabled approaches to molecular epidemiology have become essential to public health agencies and the microbial research community. We developed the algorithm STing to provide turn-key solutions for molecular typing and gene detection directly from next-generation sequence data of microbial pathogens. Our implementation of STing uses an innovative k-mer search strategy that eliminates the computational overhead associated with the time consuming steps of quality control, assembly, and alignment required by more traditional methods. We compared STing to six of the most widely used programs for genome-based molecular typing and demonstrate its ease of use, accuracy, speed, and efficiency. STing shows superior accuracy and performance for standard multilocus sequence typing schemes, along with larger genome-scale typing schemes, and it enables rapid automated detection of antimicrobial resistance and virulence factor genes. We hope that the adoption of STing will help to democratize microbial genomics and thereby maximize its benefit for public health.
Systematic analyses of factors required for adhesion ofSalmonella entericaserovar Typhimurium to corn salad (Valerianella locusta)
Authors: Elpers Laura , Kretzschmar Juliane , Nuccio Sean-Paul , Bäumler Andreas J. , Hensel Michael
Published: November 2019

Salmonella entericais a foodborne pathogen leading to gastroenteritis and is commonly acquired by consumption of contaminated food of animal origin. However, numbers of outbreaks linked to the consumption of fresh or minimally processed food of non-animal origin are increasing. New infection routes ofS. entericaby vegetables, fruits, nuts and herbs have to be considered. This leads to special interest inS. entericainteractions with leafy products, e.g. salads, that are consumed unprocessed. The attachment ofS. entericato salad is a crucial step in contamination, but little is known about the bacterial factors required and mechanisms of adhesion.S. entericapossesses a complex set of adhesive structures whose functions are only partly understood. Potentially,S. entericamay deploy multiple adhesive strategies for adhering to various salad species, and other vegetables. Here, we systematically analyzed the contribution of the complete adhesiome, of LPS, and of flagella-mediated motility ofS. entericaserovar Typhimurium (STM) in adhesion to corn salad. We deployed a reductionist, synthetic approach to identify factors involved in the surface binding of STM to leaves of corn salad with particular regard to the expression of all known adhesive structures using the Tet-on system. This work reveals the contribution of Saf fimbriae, type 1 secretion system-secreted BapA, an intact LPS, and flagella-mediated motility of STM in adhesion to corn salad leaves.

Importance

Human gastrointestinal pathogens are often transmitted by animal products, but recent outbreaks show increasing importance of vegetables as source of infection by pathogenicE. coliorSalmonella enterica.The mechanisms of binding ofS. entericato vegetables such as salad are only poorly understood. We established an experimental model system to systematically investigate the role of adhesive structures ofS. entericaserovar Typhimurium in binding to corn salad leaves. The contributions of all members of the complex adhesiome, flagella, and O-antigen were evaluated. We identified that Saf fimbriae, type 1 secretion system-secreted BapA, an intact LPS, and flagella-mediated motility contribute to adhesion ofSalmonellato corn salad leaves. These results will enable future investigations on factors contributing to contamination of vegetables under agricultural conditions.
Can we use it? On the utility ofde novoand reference-based assembly of Nanopore data for plant plastome sequencing
Authors: Scheunert Agnes , Dorfner Marco , Lingl Thomas , Oberprieler Christoph
Published: November 2019

The chloroplast genome harbors plenty of valuable information for phylogenetic research. Illumina short-read data is generally used forde novoassembly of whole plastomes. PacBio or Oxford Nanopore long reads are additionally employed in hybrid approaches to enable assembly across the highly similar inverted repeats of a chloroplast genome. Unlike for PacBio, plastome assemblies based solely on Nanopore reads are rarely found, due to their high error rate and non-random error profile. However, the actual quality decline connected to their use has never been quantified. Furthermore, no study has employed reference-based assembly using Nanopore reads, which is common with Illumina data. UsingLeucanthemumMill. as an example, we compared the sequence quality of seven plastome assemblies of the same species, using combinations of two sequencing platforms and three analysis pipelines. In addition, we assessed the factors which might influence Nanopore assembly quality during sequence generation and bioinformatic processing.

The consensus sequence derived fromde novoassembly of Nanopore data had a sequence identity of 99.59% compared to Illumina short-readde novoassembly. Most of the found errors comprise indels (81.5%), and a large majority of them is part of homopolymer regions. The quality of reference-based assembly is heavily dependent upon the choice of a close-enough reference. Using a reference with 0.83% sequence divergence from the studied species, mapping of Nanopore reads results in a consensus comparable to that from Nanoporede novoassembly, and of only slightly inferior quality compared to a reference-based assembly with Illumina data (0.49% and 0.26% divergence from Illuminade novo). For optimal assembly of Nanopore data, appropriate filtering of contaminants and chimeric sequences, as well as employing moderate read coverage, is essential.

Based on these results, we conclude that Nanopore long reads are a suitable alternative to Illumina short reads in plastome phylogenomics. Only few errors remain in the finalized assembly, which can be easily masked in phylogenetic analyses without loss in analytical accuracy. The easily applicable and cost-effective technology might warrant more attention by researchers dealing with plant chloroplast genomes.