bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of 18F-FDG PET/CT for the Evaluation of Carcinoma Arising From Choledochal Cysts
Authors: He Qiao , Zhang Linqi , Zhang Bing , Zhang Xiangsong
Published: October 2018

Choledochal cysts are rare congenital anomalies of the biliary tree, which are more prevalent in female Asian population. Malignant transformation occurs in 10% to 30% of adults with choledochal cysts. A 39-year-old man presented with abdominal pain for 2 months, with irregular thickening of bile duct wall on ultrasound and enhanced CT. Staging with 18F-FDG PET/CT demonstrated lymph node and liver metastasis. 18F-FDG PET/CT may become a valuable imaging procedure in diagnosing and staging of carcinoma arising from choledochal cysts.
18F-FDG PET/CT Revealing Constrictive Pericarditis as the Only Manifestation of Malignant Mesothelioma
Authors: Edel Jan Pieter , Balink Hans
Published: October 2018

A 57-year-old man presented with shortness of breath and ankle edema. Constrictive pericarditis with an unexplained mass surrounding the heart was diagnosed by ultrasound. Accordingly, 18F-FDG PET/CT was performed. Multiple PET-positive noduli and irregular tissue were located in the pericardium, with pleural fluid present, but without additional pulmonic or pleural pathology. A pericardiectomy was successfully performed. Histopathology and immunohistochemical staining revealed epithelioid mesothelioma.
Enchondroma of Tibia as Potential False-positive Finding on 68Ga-DOTATOC PET/CT Scan
Authors: Mahajan Sonia , Bodei Lisa , Huicochea Castellanos Sandra , Grewal Ravinder K.
Published: October 2018

A 70-year-old man with a history of carcinoid tumor of small bowel was referred for 68Ga-DOTATOC study to evaluate the extent of disease. PET/CT scan revealed known metastatic disease in the liver, with other sites of involvement including pancreas, peritoneum, and bones. In addition, moderately intense uptake was noted in proximal right tibia and further correlation on CT showed metaphyseal lesion with “rings and arcs” calcification suggestive of enchondroma. This case highlights the possibility of overexpression of somatostatin receptors in enchondromas, which has been little explored in literature.
Poorly Differentiated Primary Carcinoma of the Middle Ear on 18F-FDG PET/CT
Authors: Nemer John S. , Hsieh Meng-Chieh P. , Chen Diane , O'Toole Kathleen M. , Yeh Randy
Published: October 2018

Primary carcinoma of the middle ear is extremely rare. A 41-year-old woman with a history of skull base osteomyelitis and chronic suppurative right otitis media presented with 1 month of right-sided facial droop, tearing, and headaches. Initial head CT revealed bony destruction and soft tissue opacification involving the right middle ear. Surgical biopsy yielded poorly differentiated carcinoma. Subsequent18F-FDG PET/CT and MRI scans demonstrated FDG-avid soft tissue in the right middle ear with associated heterogeneously enhancing soft tissue on MRI.
Multiple Intravascular Papillary Endothelial Hyperplasia of Bone Mimicking Malignancy on 99mTc-MDP Bone Scan and 18F-FDG PET/CT
Authors: Tang Kun , Sun Wenwen , Lin Jie , Wang Ling
Published: October 2018

Multiple intravascular papillary endothelial hyperplasia involved with bone is rare. In this study, we present the case of a 53-year-old woman having occasional chest pains located in the middle of the sternum and the left chest wall. Multiple intravascular papillary endothelial hyperplasia lesions with high metabolism distributed in the sternum, left ribs, 12th thoracic vertebra, and left ilium on bone scintigraphy as well as PET/CT, which were easily misdiagnosed as bone malignant tumors. Increased awareness of this benign lesion and its high metabolic findings will improve preoperative diagnosis and avoid misinterpretation that may lead to an unnecessary invasive treatment.
Whole-Body Vibration Increases Cardiopulmonary Performance in the Elderly
Authors: Pessoa Maíra Florentino , Brandão Daniella Cunha , de Sá Rafaela Barros , Aguiar Maria Inês R. , de Souza Helga Cecília Muniz , de Melo Barcelar Jacqueline , Reinaux Cyda Maria Albuquerque , de Andrade Armele Dornelas
Published: October 2018

Aim:

To evaluate the effects of whole-body vibration (WBV) on ergospirometric variables in the elderly.

Methods:

A total of 31 elderly people were randomly assigned to 1 of the 3 groups—resistance, WBV, WBV + resistance—training twice per week, 3 months, evaluating ventilatory thresholds by ergospirometry and peripheral strength.

Results:

WBV groups increased

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2 after training when compared to the resistance group (25.2 ± 1.6 in WBV with P < .001 and 25.2 ± 3.2 in WBV + resistance with P < .001), as the percentage heart rate reserve (resistance = 27%; WBV = 48.4%; and WBV + resistance = 49.9%).

Conclusions:

In the elderly, WBV increased strength and

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2max, combining into a single program both aerobic and resistance workouts.
The Effect of Message Emotion and Logic on Nutritional Attitude Change as Measured by Argumentation Style in an Online Nutrition Class
Authors: Bansah Abednego K. , Moore David Richard , Holben David H.
Published: October 2018

This study investigated the effect of message credibility and the content of messages on attitude change about nutrition. Two research instruments were used for data collection. Attitude change, the dependent variable, was determined through the retrospective post- and then pretest questionnaire. A P value of less than .05 was applied to identify statistical significance. The best model developed from this study indicated that, for an effective nutritional attitudinal change, the messages should be composed of both emotion and logic in addition to credibility. This study reinforces not only the importance of message credibility and content but also the role that digital technology plays in nutrition intervention and counseling.
Validating an Evaluation Tool for Nutrition Education Handouts in the Clinical Setting
Authors: Bellini Sarah Gunnell , Shields Jessica , Eggett Dennis L.
Published: October 2018

The purpose of this study was to establish face and content validity and measure interrater reliability of an adapted version of the Developing and Assessing Nutrition Education Handouts tool for nutrition education handouts used in the clinical nutrition setting. An expert panel of 6 registered dietitian nutritionists who work in the clinical setting established face and content validity for Developing and Assessing Nutrition Education Handouts. Key criteria were identified for systematic evaluation of the nutrition education handouts. The intraclass correlation coefficient for the total score of the nutrition education handouts was 0.452. Eighteen of the 25 criteria applied to the materials had greater than 80% agreement.
Stochastic electromagnetic field propagation— measurement and modelling
Authors: Gradoni Gabriele , Russer Johannes , Baharuddin Mohd Hafiz , Haider Michael , Russer Peter , Smartt Christopher , Creagh Stephen C. , Tanner Gregor , Thomas David W. P.
Published: October 2018

This paper reviews recent progress in the measurement and modelling of stochastic electromagnetic fields, focusing on propagation approaches based on Wigner functions and the method of moments technique. The respective propagation methods are exemplified by application to measurements of electromagnetic emissions from a stirred, cavity-backed aperture. We discuss early elements of statistical electromagnetics in Heaviside's papers, driven mainly by an analogy of electromagnetic wave propagation with heat transfer. These ideas include concepts of momentum and directionality in the realm of propagation through confined media with irregular boundaries. We then review and extend concepts using Wigner functions to propagate the statistical properties of electromagnetic fields. We discuss in particular how to include polarization in this formalism leading to a Wigner tensor formulation and a relation to an averaged Poynting vector.

This article is part of the theme issue ‘Celebrating 125 years of Oliver Heaviside's ‘Electromagnetic Theory’’.
Oliver Heaviside's electromagnetic theory
Authors: Donaghy-Spargo Christopher , Yakovlev Alex
Published: October 2018

The year 2018 marks the 125th anniversary of the first of three published volumes on electromagnetic theory by the eminent Victorian electrical engineer, physicist and mathematician, Oliver Heaviside FRS. This commemorative issue of
Philosophical Transactions of the Royal Society A
celebrates the publication of this work by collecting papers on a broad spectrum across the field of electromagnetic theory, including innovative research papers interspersed between historical perspectives and relevant reviews. Heaviside was a remarkable man, an original thinker with brilliant mathematical powers and physical insight who made many significant contributions in his fields of interest, though he is remembered primarily for his ‘step function’, commonly used today in many branches of physics, mathematics and engineering. Here, we celebrate the man and his work by illustrating his major contributions and highlighting his great success in solving some of the great telegraphic engineering problems of the Victorian era, in part due to his development and detailed understanding of the governing electromagnetic theory. We celebrate his
Electromagnetic theory
: three volumes of insights, techniques and understanding from mathematical, physical and engineering perspectives—as dictated by J. C. Maxwell FRS, but interpreted, reformulated and expanded by Heaviside to advance the art and science of electrical engineering beyond all expectations.

This article is part of the theme issue ‘Celebrating 125 years of Oliver Heaviside's ‘Electromagnetic Theory’’.
Signatures of cell death and proliferation in perturbation transcriptomics data - from confounding factor to effective prediction
Authors: Szalai Bence , Subramanian Vigneshwari , Alföldi Róbert , Puskás László G. , Saez-Rodriguez Julio
Published: October 2018

Transcriptomics perturbation signatures are valuable data sources for functional genomic studies. They can be effectively used to identify mechanism of action for new compounds and to infer functional activity of different cellular processes. Linking perturbation signatures to phenotypic studies opens up the possibility to model selected cellular phenotypes from gene expression data and to predict drugs interfering with the phenotype. At the same time, close association of transcriptomics changes with phenotypes can potentially mask the compound specific signatures. By linking perturbation transcriptomics data from the LINCS-L1000 project with cell viability phenotypic information upon genetic (from Achilles project) and chemical (from CTRP screen) perturbations for more than 90,000 signature - cell viability pairs, we show here that a cell death signature is a major factor behind perturbation signatures. We use this relationship to effectively predict cell viability from transcriptomics signatures, and identify and experimentally validate compounds that induce either cell death or proliferation. We also show that cellular toxicity can lead to an unexpected similarity of toxic compound signatures confounding the mechanism of action discovery. Consensus compound signatures predict cell-specific anti-cancer drug sensitivity, even if the drug signature is not measured in the same cell line. These signatures outperform conventional drug-specific features like nominal target and chemical fingerprints. Our results can help removing confounding factors of large scale transcriptomics perturbation screens and show that expression signatures boost prediction of drug sensitivity.
Mouse Genome-Wide Association and Systems Genetics IdentifiesLhfpas a Regulator of Bone Mass
Authors: Mesner Larry D. , Calabrese Gina , Al-Barghouthi Basel , Gatti Daniel M. , Sundberg John P. , Churchill Gary A. , Godfrey Dana. A. , Ackert-Bicknell Cheryl L. , Farber Charles R.
Published: October 2018

Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P=3.1 x 10−12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two seperate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes;Gm2447, Gm20750, Cog6, andLhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts and its expression was regulated by local expression QTL (eQTL) in multiple tissues. A co-expression network analysis revealed thatLhfpwas strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone,Lhfpdeficient mice (Lhfp−/−) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) fromLhfp−/−displayed increased osteogenic differentiation.Lfhp−/−mice also had elevated BMD due to increased cortical bone mass. In conclusion, we used GWAS and systems genetics in mice to identifyLhfpas a regulator of osteoblast activity and bone mass.
Therapeutic blockade of Activin-A improves NK cell function and anti-tumor immunity
Authors: Rautela Jai , Dagley Laura F. , Schuster Iona S. , Hediyeh-Zadeh Soroor , Delconte Rebecca B. , Cursons Joseph , Hennessy Robert , Hutchinson Dana S. , Harrison Craig , de Oliveira Carolina C. , Vivier Eric , Webb Andrew I. , Degli-Esposti Mariapia A. , Davis Melissa J. , Huntington Nicholas D. , Souza-Fonseca-Guimaraes Fernando
Published: October 2018

Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)-β is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. In this report, we show that NK cells express the type I Activin receptor, ALK4, which upon binding its ligand Activin-A, phosphorylates SMAD2/3 to efficiently suppress IL-15-mediated NK cell metabolism. Activin-A impairs human and mouse NK cell proliferation and downregulates intracellular granzyme B levels to impair tumor killing. Similar to TGF-β, Activin-A also induced SMAD2/3 phosphorylation and drove NK cells to upregulate several ILC1-like surface markers including CD69, TRAIL and CD49a. Activin-A also induced these changes on TGF-β receptor deficient NK cells, highlighting that Activin-A and TGF-β are independent pathways that drive SMAD2/3-mediated NK cell suppression. Finally, therapeutic inhibition of Activin-A by Follistatin significantly slowed orthotopic melanoma growth in mice. These data highlight independent SMAD2/3 pathways target NK cell fitness and function and identify a novel therapeutic axis to promote tumor immunity.

One Sentence Summary:Activin-A can directly inhibit NK cell effector functions, promote NK cells transdifferentiation into ILC1-like cells and suppress anti-melanoma immunity.
Dynamic evolutionary history and gene content of sex chromosomes across diverse songbirds
Authors: Xu Luo-hao , Auer Gabriel , Peona Valentina , Suh Alexander , Deng Yuan , Feng Shao-hong , Zhang Guo-jie , Blom Mozes P.K. , Christidis Les , Prost Stefan , Irestedt Martin , Zhou Qi
Published: October 2018

Songbirds have a species number almost equivalent to that of mammals, and are classic models for studying mechanisms of speciation and sexual selection. Sex chromosomes are hotspots of both processes, yet their evolutionary history in songbirds remains unclear. To elucidate that, we characterize female genomes of 11 songbird species having ZW sex chromosomes, with 5 genomes of bird-of-paradise species newly produced in this work. We conclude that songbird sex chromosomes have undergone at least four steps of recombination suppression before their species radiation, producing a gradient pattern of pairwise sequence divergence termed ‘evolutionary strata’. Interestingly, the latest stratum probably emerged due to a songbird-specific burst of retrotransposon CR1-E1 elements at its boundary, or chromosome inversion on the W chromosome. The formation of evolutionary strata has reshaped the genomic architecture of both sex chromosomes. We find stepwise variations of Z-linked inversions, repeat and GC contents, as well as W-linked gene loss rate that are associated with the age of strata. Over 30 W-linked genes have been preserved for their essential functions, indicated by their higher and broader expression of orthologs in lizard than those of other sex-linked genes. We also find a different degree of accelerated evolution of Z-linked genes vs. autosomal genes among different species, potentially reflecting their diversified intensity of sexual selection. Our results uncover the dynamic evolutionary history of songbird sex chromosomes, and provide novel insights into the mechanisms of recombination suppression.
Wolbachia pipientisoccurs inAedes aegyptipopulations in New Mexico and Florida, USA
Authors: Kulkarni Aditi , Yu Wanqin , Jiang Jinjin , Sanchez Concepcion , Karna Ajit K. , Martinez Kalli J.L. , Hanley Kathryn A. , Buenemann Michaela , Hansen Immo A. , Xue Rui-de , Ettestad Paul , Melman Sandra , Duguma Dagne , Debboun Mustapha , Xu Jiannong
Published: October 2018

The mosquitoesAedes aegypti(L.) andAe. albopictusSkuse are the major vectors of dengue, Zika, yellow fever and chikungunya viruses worldwide.Wolbachia, an endosymbiotic bacterium present in many insects, is being utilized in novel vector control strategies to manipulate mosquito life history and vector competence to curb virus transmission. Earlier studies have found thatWolbachiais commonly detected inAe.albopictusbut rarely detected inAe. aegypti. In this study, we used a two-step PCR assay to detectWolbachiain wild-collected samples ofAe. aegypti.The PCR products were sequenced to validate amplicons and identifyWolbachiastrains. A loop-mediated isothermal amplification (LAMP) assay was developed and used for detectingWolbachiain selected mosquito specimens as well. We foundWolbachiain 85/148 (57.4%) wildAe. aegyptispecimens from various cities in New Mexico and in 2/46 (4.3%) from St. Augustine, Florida. We did not detectWolbachiain 94 samples ofAe. aegyptifrom Deer Park, Harris County, Texas.Wolbachiadetected inAe. aegyptifrom both New Mexico and Florida was thewAlbB strain ofWolbachia pipientis.AWolbachiapositive colony ofAe. aegyptiwas established from pupae collected in Las Cruces, New Mexico in 2018. The infected females of this strain transmittedWolbachiato their progeny when crossed with males of Rockefeller strain ofAe. aegypti, which does not carryWolbachia.In contrast, none of the progeny of progeny of Las Cruces males mated to Rockefeller females were infected withWolbachia.
Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of breast cancer
Authors: Tőkés Anna-Mária , Rusz Orsolya , Cserni Gábor , Tóth Erika , Rubovszky Gábor , Tőkés Tímea , Vízkeleti Laura , Reiniger Lilla , Kószó Renáta , Kahán Zsuzsanna , Kulka Janina , Donia Marco , Vörös András , Szallasi Zoltan
Published: October 2018

Background

Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes, but the clinical relevance of this triggered immune response is not known.

We decided to investigate, whether treatment with various chemotherapeutic agents with significantly different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in the clinical setting.

Methods

112 breast carcinoma cases treated with pre-operative chemotherapy were selected for the study. According to chemotherapy regimen 28/112 patients received platinum-based, 42/112 cyclophosphamide-based and 42/112 anthracycline-based chemotherapy. The percentage of stromal tumor-infiltrating lymphocytes (StrTIL) was evaluated on hematoxylineosin stained slides of pre-treatment core biopsy (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL), according to the most recent recommendation of International TILs Working Group. In survival analyses, TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.

Results

Of the 112 cases, 58.0% (n=65) were hormone receptor (HR) positive and 42.0% (n=47) were HR negative. There was a trend of higher post-StrTIL compared to pre-StrTIL (median 6.25% vs. 3.00%; p<0.001). When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we experienced significant StrTIL increase independently of the treatment applied. Based on the results of survival analyses both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Each 1% increase in post-StrTIL reduced the hazard of distant metastases development by 2.6% (hazard ratio: 0.974; CI: 0.948-1.000; p=0.05) and for each 1% ΔStrTIL increment, the risk of distant metastases was reduced by 4.3% (hazard ratio: 0.957; CI: 0.932-0.983; p=0.001). The prognostic role of StrTIL in HR positive cases could not be proven.

Conclusions

StrTIL expression might be stimulated by highly (platinum), moderately (cyclophosphamide) and marginally (taxane, anthracycline) mutagenic chemotherapeutic agents. Increase in StrTIL in residual cancer compared to pre-treatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.
Trophic consistency of supraspecific taxa in belowground invertebrate communities
Authors: Potapov Anton M. , Scheu Stefan , Tiunov Alexei V.
Published: October 2018

1. Animals that have similar morphological traits are expected to share similar ecological niches. This statement applies to individual animals within a species and thus species often serve as the functional units in ecological studies. Species are further grouped into higher-ranked taxonomic units based on their morphological similarity and thus are also expected to be ecologically similar. On the other hand, theory predicts that strong competition between closely related species can lead to differentiation of ecological niches. Due to a high diversity and limited taxonomic expertise, soil food webs are often resolved using supraspecific taxa such as families, orders or even classes as functional units.

2. Here we for the first time empirically tested the trophic consistency of supraspecific taxa across major lineages of temperate forest soil invertebrates: Annelida, Chelicerata, Myriapoda, Crustacea and Hexapoda. Published data on stable isotope compositions of carbon and nitrogen were used to infer basal resources and trophic level, and explore the relationship between taxonomic and trophic dissimilarity of local populations.

3. Genera and families had normal and unimodal distributions of isotope niches, suggesting that supraspecific taxa are trophically consistent. The isotopic niche of populations across different localities is better predicted by species than by supraspecific taxa. However, within the same genus, the effect of species identity on stable isotope composition of populations was not significant in 92% of cases. The link to basal resources, i.e. plants or detritus, was convergent in different lineages, while trophic levels followed the Brownian motion taxonomic model. Virtually none of the studied taxa showed pronounced trophic niche conservatism within a lineage.

4. Supraspecific taxa are meaningful as functional units in ecological studies, but the consistency varies among taxa and thus the choice of taxonomic resolution depends on the research question; generally, identification of taxa should be more detailed in more diverse taxonomic groups. We compiled a comprehensive list of mean Δ13C and Δ15N values of invertebrate taxa from temperate forest soils allowing to refine soil food-web models when identification to species level is not feasible.
Seizure-associated spreading depression is a major feature of ictal events in two animal models of chronic epilepsy
Authors: Bahari Fatemeh , Ssentongo Paddy , Liu Jiayang , Kimbugwe John , Curay Carlos , Schiff Steven J. , Gluckman Bruce J.
Published: October 2018

Spreading depression is characterized by slow, propagating wave of cellular depolarization (SD) and is wildly associated with migraine, stroke, and traumatic brain injury. Seizures and spreading depression (or spreading depolarization, SD) have long been reported to coincide in acute seizure induction experiments. However, SD has not been observed associated with spotaneous seizures in animal or clinical recordings. Recently, advances in acquisition systems for neurointensive care units have made routine observations of SD possible. In clinical epilepsy, SD has been suggested as a candidate mechanism for migraine/headache like events following seizures as well as for post-ictal generalized suppression. In animal models of epilepsy, seizure-induced brainstem SD has also been demonstrated as a mechanism of sudden unexplained death in epilepsy (SUDEP). The interplay between seizures and SD has also been suggested in computational models, where the two are components of the repetoir of neuronal activity.

However, the spatiotemporal dynamics of SD with respect to spontaneous seizures in chronically epileptic brain remains ambigous. We analyzed continuous long-term DC sensitive EEG measurements from two fundamentally different animal models of chronic epilepsy. We found that SD was associated with approximately one-third of all spontaneous seizures in each model. Additionally, SDs participated in the organization of seizure clusters. These findings demonstrate that the underlying dynamic of epileptic events is broader than seizures alone.

Significance Statement

Spreading depression is characterized by slow, propagating wave of cellular spreading depolarization (SD) and is wildly associated with migraine, stroke, and traumatic brain injury. Although recently the linkage between SD and induced seizures has been recognized, the mechanistic relationship between SD and spontaneous seizures remains poorly understood. Here, we utilized long-term, stable, near-DC measurements of the brain activity in two fundamentally different animal models of epilepsy to investigate the SD-seizure interplay. We found that SD is a frequent phenomenon in the epileptic brain, in these models is associated with more than a third of all seizures, and appears to connect seizures in seizure clusters. Although in one model SD stereotypically propagates out from a single focus in the hippocampus, depression of the field-potentials is observed synchronously across much of the hippocampus. These observations highlight the value of stable DC measurements for accurate understanding of SD and its propagation. We found that spontaneous ictal events that include both seizures and SD are frequent in animal models of epilepsy. These findings suggest that SD could be a valuable target for treatment and control of epilepsy.
Nuclease dead Cas9 is a programmable roadblock for DNA replication
Authors: Whinn Kelsey , Kaur Gurleen , Lewis Jacob S. , Schauer Grant , Müller Stefan , Jergic Slobodan , Maynard Hamish , Yan Gan Zhong , Naganbabu Matharishwan , Bruchez Marcel P. , O’Donnell Michael E. , Dixon Nicholas E. , van Oijen Antoine M. , Ghodke Harshad
Published: October 2018

DNA replication occurs on chromosomal DNA while processes such as DNA repair, recombination and transcription continue. However, we have limited experimental tools to study the consequences of collisions between DNA-bound molecular machines. Here, we repurpose a catalytically inactivated Cas9 (dCas9) construct fused to the photo-stable dL5 protein fluoromodule as a novel, targetable protein-DNA roadblock for studying replication fork arrest at the single-molecule levelin vitroas well asin vivo. We find that the specifically bound dCas9–guideRNA complex arrests viral, bacterial and eukaryotic replication forksin vitro.
Discovery and functional annotation of quantitative trait loci affecting resistance to sea lice in Atlantic salmon
Authors: Robledo Diego , Gutiérrez Alejandro P. , Barría Agustín , Lhorente Jean P. , Houston Ross D. , Yáñez José M.
Published: October 2018

Sea lice (Caligus rogercresseyi) are ectoparasitic copepods which have a large negative economic and welfare impact in Atlantic salmon (Salmo salar) aquaculture, particularly in Chile. A multi-faceted prevention and control strategy is required to tackle lice, and selective breeding contributes via cumulative improvement of host resistance to the parasite. While host resistance has been shown to be heritable, little is yet known about the individual loci that contribute to this resistance, the potential underlying genes, and their mechanisms of action. In this study we took a multifaceted approach to identify and characterise quantitative trait loci (QTL) affecting hose resistance in a population of 2,688 Caligus-challenged Atlantic salmon post-smolts from a commercial breeding programme. We used low and medium density genotyping to collect genome-wide SNP marker data for all animals. Moderate heritablility estimates of 0.28 and 0.24 were obtained for lice density (as a measure of host resistance) and growth during infestation respectively. Three QTL explaining between 7 and 13 % of the genetic variation in resistance to sea lice (as represented by the traits of lice density) were detected on chromosomes 3, 18 and 21. Characterisation of these QTL regions was undertaken using RNA sequencing and pooled whole genome sequencing data. This resulted in the identification of a shortlist of potential underlying causative genes, and candidate functional mutations for further study. For example, candidates within the chromosome 3 QTL include a putative premature stop mutation in TOB1 (an anti-proliferative transcription factor involved in T cell regulation) and an uncharacterized protein which showed significant differential allelic expression (implying the existence of a cis-acting regulatory mutation). While host resistance to sea lice is polygenic in nature, the results of this study highlight significant QTL regions together explaining a moderate proportion of the heritability of the trait. Future investigation of these QTL may enable improved knowledge of the functional mechanisms of host resistance to sea lice, and incorporation of functional variants to improve genomic selection accuracy.
The CryoEM Structure of the Ribosome Maturation Factor Rea1
Authors: Sosnowski Piotr , Urnavicius Linas , Boland Andreas , Fagiewicz Robert , Busselez Johan , Papai Gabor , Schmidt Helgo
Published: October 2018

The biogenesis of the 60S ribosomal subunit is initiated in the nucleus where rRNAs and proteins form pre-60S particles. These pre-60S particles mature by transiently interacting with various assembly factors. The ~5000 amino-acid AAA+ ATPase Rea1 (or Midasin) generates force to mechanically remove assembly factors from pre-60S particles, which promotes their export to the cytosol. Here we present three Rea1 cryoEM structures. We visualize the Rea1 engine, a hexameric ring of AAA+ domains, and identify an α-helical bundle of AAA2 as a major ATPase activity regulator. The α-helical bundle interferes with nucleotide induced conformational changes that create a docking site for the substrate binding MIDAS domain of Rea1 on the AAA+ ring. Furthermore, we reveal the architecture of the Rea1 linker, which is involved in force generation and extends from the AAA+ ring. The data presented here provide insights into the mechanism of one of the most complex ribosome maturation factors.
Single synapse indicators of impaired glutamate clearance derived from fast iGluu imaging of cortical afferents in the striatum of normal and Huntington (Q175) mice
Authors: Dvorzhak Anton , Helassa Nordine , Török Katalin , Schmitz Dietmar , Grantyn Rosemarie
Published: October 2018

Changes in the balance between glutamate (Glu) release and uptake may stimulate synaptic reorganization and even synapse loss. In the case of neurodegeneration, a mismatch between astroglial Glu uptake and presynaptic Glu release could be detected if both parameters were assessed independently and at a single synapse level. This has now become possible due to a new imaging assay with the genetically encoded ultrafast Glu sensor iGluu. We report findings from individual corticostriatal synapses in acute slices prepared from mice aged >1 year. Contrasting patterns of short-term plasticity and a size criterion identified 2 classes of terminals, presumably corresponding to the previously defined IT and PT synapses. The latter exhibited a higher degree of frequency potentiation/residual Glu accumulation and were selected for our first iGluu single synapse study in Q175 mice, a model of Huntington’s disease (HD). It was found that in HD the time constant of perisynaptic [Glu] decay (TauD, as indicator of uptake) and the peak iGluu amplitude (as indicator of release) were prolonged and reduced, respectively. Treatment of WT preparations with the astrocytic Glu uptake blocker TFB-TBOA (100 nM) mimicked the TauD changes in homozygotes (HOM). Considering the largest TauD values encountered in WT, about 40% of PT terminals tested in Q175 heterozygotes (HET) can be classified as dysfunctional. Moreover, HD but not WT synapses exhibited a positive correlation between TauD and the peak amplitude of iGluu. Finally, EAAT2 immunoreactivity was reduced next to corticostriatal terminals. Thus, astrocytic Glu transport remains a promising target for therapeutic intervention.

SIGNIFICANCE STATEMENT

Alterations in astrocytic Glu uptake can play a role in synaptic plasticity and neurodegeneration. Until now, sensitivity of synaptic responses to pharmacological transport block and the resulting activation of NMDA receptors were regarded as reliable evidence for a mismatch between synaptic uptake and release. But the latter parameters are interdependent. Using a new genetically encoded sensor to monitor [Glu] at individual corticostriatal synapses we can now quantify the time constant of perisynaptic [Glu] decay (as indicator of uptake) and the maximal [Glu] elevation next to the active zone (as indicator of Glu release). The results provide a positive answer to the hitherto unresolved question whether neurodegeneration (e.g. Huntington’s disease) associates with a glutamate uptake deficit at tripartite excitatory synapses.
Live cell bioimaging with carbon dots produced in situ by femtosecond laser from intracellular material
Authors: Shakhov Aleksander M. , Astafiev Artyom A. , Osychenko Alina A. , Syrchina Maria S. , Nadtochenko Viktor A.
Published: October 2018

Owning to excellent optical properties and high biocompatibility carbon dots (CDs) have drawn increasing attention and have been widely applied as imaging agents for various bio-applications. Here we report a strategy for live-cell fluorescent bioimaging based on in situ synthesis of CDs within cells by tightly focused femtosecond laser pulses. Laser-produced carbon dots exhibit bright excitation-dependent fluorescence and are highly two-photon active under near infrared femtosecond excitation, thus demonstrating a potential for two-photon fluorescence imaging. The Raman spectra of fluorescent centers show strong D (1350 cm-1) and G (1590 cm-1) bands, thus suggesting that they are composed of carbon dots with sp2-hybridized core. Using Mouse GV oocytes as a model system we examine cytotoxicity and demonstrate the possibility of long-term fluorescent intracellular tracking of the laser-produced CDs. Created virtually in any point of the live cell, CD-based fluorescent μm-sized markers demonstrate high structural stability and retain bright fluorescence many hours after formation. Our results point to laser-produced fluorescent CDs as a highly-potent tool for cell cycle tracking, culture cell marking and probing intracellular movements.
Diversification of giant and large eukaryotic dsDNA viruses predated the origin of modern eukaryotes
Authors: Guglielmini Julien , Woo Anthony , Krupovic Mart , Forterre Patrick , Gaia Morgan
Published: October 2018

Giant and large eukaryotic double-stranded DNA viruses from the Nucleo-Cytoplasmic Large DNA Virus (NCLDV) assemblage represent a remarkably diverse and potentially ancient component of the eukaryotic virome. However, their origin(s), evolution and potential roles in the emergence of modern eukaryotes remain a subject of intense debate. Since the characterization of the mimivirus in 2003, many big and giant viruses have been discovered at a steady pace, offering a vast material for evolutionary investigations. In parallel, phylogenetic tools are constantly being improved, offering more rigorous approaches for reconstruction of deep evolutionary history of viruses and their hosts. Here we present robust phylogenetic trees of NCLDVs, based on the 8 most conserved proteins responsible for virion morphogenesis and informational processes. Our results uncover the evolutionary relationships between different NCLDV families and support the existence of two superclades of NCLDVs, each encompassing several families. We present evidence strongly suggesting that the NCLDV core genes, which are involved in both informational processes and virion formation, were acquired vertically from a common ancestor. Among them, the largest subunits of the DNA-dependent RNA polymerase were seemingly transferred from two clades of NCLDVs to proto-eukaryotes, giving rise to two of the three eukaryotic DNA-dependent RNA polymerases. Our results strongly suggest that these transfers and the diversification of NCLDVs predated the emergence of modern eukaryotes, emphasizing the major role of viruses in the evolution of cellular domains.
A focus on details? Inconsistent results on auditory and visual local-to-global processing in absolute pitch musicians
Authors: Wenhart T. , Altenmüller E.
Published: October 2018

Absolute pitch, the ability to name or produce a musical tone without a reference, is a rare ability which is often related to early musical training and genetic components. However, it remains a matter of debate why absolute pitch is relatively common in autism spectrum disorders and why absolute pitch possessors exhibit higher autistic traits. By definition absolute pitch (which involves the analysis of single tones) is characterized by a focus on a local scale than relative pitch (involving relations between tones, intervals, melodies).

This study investigated whether a detail-oriented cognitive style, a concept borrowed from the autism literature (weak central coherence theory), might provide a framework to explain this joint occurrence. Two local-to-global experiments in vision (hierarchically constructed letters) and audition (hierarchically constructed melodies) as well as a pitch adjustment test measuring absolute pitch proficiency were conducted in 31 absolute pitch and 33 relative pitch professional musicians. Analyses revealed inconsistent group differences among reaction time, accuracy and speed-accuracy-composite-scores of experimental conditions (local vs. global, and congruent vs. incongruent stimuli). Furthermore, amounts of interference of global form on judgements of local elements and vice versa were calculated. Interestingly, reduced global-to-local interference in audition was associated with greater absolute pitch ability and in vision with higher autistic traits. Results are partially in line with the idea of a detail-oriented cognitive style in absolute pitch musicians. The inconsistency of the results might be due to limitations of global-to-local paradigms in measuring cognitive style and due to heterogeneity of absolute pitch possessors. In summary, this study provides further evidence for a multifaceted pattern of various and potentially interacting factors on the acquisition of absolute pitch.
Specialized and spatially organized coding of sensory, motor, and cognitive variables in midbrain dopamine neurons
Authors: Engelhard Ben , Finkelstein Joel , Cox Julia , Fleming Weston , Jang Hee Jae , Ornelas Sharon , Koay Sue Ann , Thiberge Stephan , Daw Nathaniel , Tank David W. , Witten Ilana B.
Published: October 2018

There is increased appreciation that dopamine (DA) neurons in the midbrain respond not only to reward 1,2 and reward-predicting cues 1,3,4, but also to other variables such as distance to reward 5, movements 6–11 and behavioral choices 12–15. Based on these findings, a major open question is how the responses to these diverse variables are organized across the population of DA neurons. In other words, do individual DA neurons multiplex multiple variables, or are subsets of neurons specialized in encoding specific behavioral variables? The reason that this fundamental question has been difficult to resolve is that recordings from large populations of individual DA neurons have not been performed in a behavioral task with sufficient complexity to examine these diverse variables simultaneously. To address this gap, we used 2-photon calcium imaging through an implanted lens to record activity of >300 midbrain DA neurons in the VTA during a complex decision-making task. As mice navigated in a virtual reality (VR) environment, DA neurons encoded an array of sensory, motor, and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioral variables, in addition to encoding reward. These functional clusters were spatially organized, such that neighboring neurons were more likely to be part of the same cluster. Taken together with the topography between DA neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by DA neurons.
Engineered developmental niche enables predictive phenotypic screening in human dystrophic cardiomyopathy
Authors: Macadangdang Jesse R. , Miklas Jason W. , Smith Alec S.T. , Choi Eunpyo , Leung Winnie , Wang Yuliang , Guan Xuan , Lee Soowan , Salick Max R. , Regnier Michael , Mack David , Childers Martin K. , Ruohola-Baker Hannele , Kim Deok-Ho
Published: October 2018

Directed differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes typically produces cells with structural, functional, and biochemical properties that most closely resemble those present in the fetal heart. Here we establish an in vitro engineered developmental cardiac niche to produce matured hPSC-derived cardiomyocytes (hPSC-CMs) with enhanced sarcomere development, electrophysiology, contractile function, mitochondrial capacity, and a more mature transcriptome. When this developmental cardiac niche was applied to dystrophin mutant hPSC-CMs, a robust disease phenotype emerged, which was not observed in non-matured diseased hPSC-CMs. Matured dystrophin mutant hPSC-CMs exhibited a greater propensity for arrhythmia as measured via beat rate variability, most likely due to higher resting cytosolic calcium content. Using a custom nanopatterned microelectrode array platform to screen functional output in hPSC-CMs exposed to our engineered developmental cardiac niche, we identified calcium channel blocker, nitrendipine, mitigated hPSC-CM arrhythmogenic behavior and correctly identified sildenafil as a false positive. Taken together, we demonstrate our developmental cardiac niche platform enables robust hPSC-CM maturation allowing for more accurate disease modeling and predictive drug screening.
An Efficient Computational Approach for Constructing the Allele Frequency Spectrum of Populations with Arbitrary Complex History
Authors: Chen Hua
Published: October 2018

The allele frequency spectrum (AFS), or site frequency spectrum, is commonly used to summarize the genomic polymorphism pattern of a sample, which is informative for inferring population history and detecting natural selection. Recently, Chen and Chen (2013) developed a method for analytically deriving the AFS for populations with temporally varying size through the coalescence time-scaling function. However, their approach is only applicable for population history scenarios in which the analytical form of the time-scaling function is tractable. In this paper, we propose a computational approach to extend the method to populations with arbitrary complex history by numerically approximating the time-scaling function. We demonstrate the performance of the approach by constructing the AFS for two population history scenarios: the logistic growth model and the Gompertz growth model, for which the AFS are unavailable with existing approaches.
Pentatricopeptide repeat poly(A) binding protein from mitochondria of trypanosomes
Authors: Mesitov Mikhail V. , Yu Tian , Suematsu Takuma , Sement Francois M. , Zhang Liye , Yu Clinton , Huang Lan , Aphasizheva Inna
Published: October 2018

In Trypanosoma brucei, most mitochondrial mRNAs undergo U-insertion/deletion editing, and 3′ adenylation and uridylation. The internal sequence changes and terminal extensions are coordinated: Pre-editing addition of the short (A) tail protects the edited transcript against 3′-5′ degradation, while post-editing A/U-tailing renders mRNA competent for ribosome recruitment. Participation of a poly(A) binding protein (PABP) in coupling of editing and 3′ modification processes has been inferred, but its identity and mechanism of action remained elusive. We report identification of KPAF4, a pentatricopeptide repeat-containing PABP which sequesters the A-tail and impedes exonucleolytic degradation. Conversely, KPAF4 inhibits uridylation of A-tailed transcripts and, therefore, premature A/U-tailing of partially-edited mRNAs. This quality check point prevents translation of incompletely edited mRNAs. Our findings also implicate the RNA editing substrate binding complex (RESC) in mediating the interaction between the 5′ end bound pyrophosphohydrolase MERS1 and 3′ end associated KPAF4 to enable mRNA circularization. This event is critical for transcript stability during the editing process.
Crystal structure, interaction energies and experimental electron density of the popular drug ketoprophen
Authors: Pawlędzio Sylwia , Makal Anna , Trzybiński Damian , Woźniak Krzysztof
Published: October 2018

The crystal and molecular structure of the pure (S)-enantiomer of the popular analgesic and anti-inflammatory drug ketoprophen (α-ket) is reported. A detailed aspherical charge-density model based on high-resolution X-ray diffraction data has been refined, yielding a high-precision geometric description and classification of the O—H...O interactions as medium strength hydrogen bonds. The crystal structure of the racemic form of ketoprophen (β-ket) was also redetermined at 100 K, at 0.5 Å resolution. A previously unreported disorder (10% occupancy) was discovered. In contrast to the racemic β-ket case, the (S)-enantiomer crystallizes with two independent molecules in the asymmetric unit with two distinct conformations. The major difference between the β-ket and α-ket crystal forms lies in the formation of distinct hydrogen-bonded motifs: a closed ring motif in β-ketversusinfinite chains of hydrogen bonds in the chiral α-ket structure. However, the overall crystal packing of both forms is surprisingly similar, with close-packed layers of antiparallel-oriented benzophenone moieties bound by C—H...π interactions. Notably, the most important stabilizing term in the total lattice energies in both instances proved to be the dispersion related to these interactions. Both forms of the title compound (α- and β-ket) were additionally characterized by differential scanning calorimetry and thermogravimetric analysis.