bluuebunny/crossref_metadata_2025 huggingface dataset:
Share, but unequally: a plausible mechanism for emergence and maintenance of intratumour heterogeneity
Authors: Li Xin , Thirumalai D.
Published: January 2019

Intratumour heterogeneity (ITH), referring to the coexistence of different cell subpopulations in a single tumour, has been a major puzzle in cancer research for almost half a century. The lack of understanding of the underlying mechanism of ITH hinders progress in developing effective therapies for cancers. Based on the findings in a recent quantitative experiment on pancreatic cancer, we developed a general evolutionary model for one type of cancer, accounting for interactions between different cell populations through paracrine or juxtacrine factors. We show that the emergence of a stable heterogeneous state in a tumour requires an unequal allocation of paracrine growth factors (public goods) between cells that produce them and those that merely consume them. Our model provides a quantitative explanation of recent
in vitro
experimental studies in pancreatic cancer in which insulin-like growth factor II (IGF-II) plays the role of public goods. The calculated phase diagrams as a function of exogenous resources and fraction of growth factor producing cells show ITH persists only in a narrow range of concentration of exogenous IGF-II. Remarkably, maintenance of ITH requires cooperation among tumour cell subpopulations in harsh conditions, specified by lack of exogenous IGF-II, whereas surplus exogenous IGF-II elicits competition. Our theory also quantitatively accounts for measured
in vivo
tumour growth in glioblastoma multiforme (GBM). The predictions for GBM tumour growth as a function of the fraction of tumour cells are amenable to experimental tests. The mechanism for ITH also provides hints for devising efficacious therapies.
Optical clearing of living brains with MAGICAL to extendin vivoimaging
Authors: Iijima Kouichirou , Oshima Takuto , Kawakami Ryosuke , Nemoto Tomomi
Published: January 2019

To understand brain functions, it is important to observe directly how multiple neural circuits are performing in living brains. However, due to tissue opaqueness, observable depth and spatiotemporal resolution are severely degradedin vivo. Here, we propose an optical brain clearing method forin vivofluorescence microscopy, termed MAGICAL (Magical Additive Glycerol Improves Clear Alive Luminance). MAGICAL enabled two-photon microscopy to capture vivid images with fast speed, at cortical layer V and hippocampal CA1in vivo. Moreover, MAGICAL promoted conventional confocal microscopy to visualize finer neuronal structures including synaptic boutons and spines in unprecedented deep regions, without intensive illumination leading to phototoxic effects. Fluorescence Emission Spectrum Transmissive Analysis (FESTA) showed that MAGICAL improvedin vivotransmittance of shorter wavelength light, which is vulnerable to optical scattering thus unsuited forin vivomicroscopy. These results suggest that MAGICAL would transparentize living brains via scattering reduction.
TaxonKit: a cross-platform and efficient NCBI taxonomy toolkit
Authors: Shen Wei , Xiong Jie
Published: January 2019

TaxonKit is a command-line toolkit for rapid manipulation of NCBI taxonomy data. It provides executable binary files for major operating systems including Windows, Linux, and Mac OS X, and can be directly used without any dependencies nor local database buiding. TaxonKit demonstrates competitive performance in execution time compared to similar tools. The efficiency, scalability, and usability of TaxonKit enable researchers to rapidly investigate taxonomy data.

Availability

Taxonkit is implemented in Go programming language. It is open-source and freely available for download and use from https://github.com/shenwei356/taxonkit.
Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts
Authors: Ahola-Olli Ari V. , Mustelin Linda , Kalimeri Maria , Kettunen Johannes , Jokelainen Jari , Auvinen Juha , Puukka Katri , Havulinna Aki S. , Lehtimäki Terho , Kähönen Mika , Juonala Markus , Keinänen-Kiukaanniemi Sirkka , Salomaa Veikko , Perola Markus , Järvelin Marjo-Riitta , Ala-Korpela Mika , Raitakari Olli , Würtz Peter
Published: January 2019

Objective

Advances in metabolomics now allow high-throughput biomarker profiling of large population studies. We aimed to identify circulating metabolic biomarkers predictive of type 2 diabetes in young adults.

Methods

Nuclear magnetic resonance metabolomics was used to quantify 229 metabolic measures in 11,896 individuals from four Finnish cohorts (mean age 33 years, range 24–45). Associations between baseline metabolites and risk of type 2 diabetes onset during 8–15 years of follow-up (392 incident cases) were assessed by logistic regression adjusted for sex, age, body mass index, and fasting glucose.

Results

Out of 229 metabolic measures, 113 were associated with incident diabetes in meta-analysis of the four cohorts (P<0.0009; odds ratios per 1-SD: 0.59–1.50). Among the strongest predictors of diabetes risk were branched-chained and aromatic amino acids (odds ratios 1.31–1.33), triglyceride fractions within the largest very-low-density lipoprotein particles (VLDL; odds ratios 1.33–1.50)), as well as linoleic omega-6 fatty acids (odds ratio 0.75) and free cholesterol in large high-density lipoprotein particles (HDL; odds ratio 0.59). A biomarker score comprised of phenylalanine, free cholesterol in large HDL, and the ratio of cholesteryl esters to total lipids in large VLDL was predictive of the risk for future diabetes in an independent validation cohort (odds ratio 10.1 [95% confidence intervals 4.2-24.1] comparing individuals in upper vs lower fifth of biomarker score). Adjustment for routine lipids and insulin attenuated the odds ratio to 5.8 [2.2-15.1].

Conclusions

Metabolic aberrations across multiple molecular pathways are predictive of the long-term risk of type 2 diabetes in young adults. Comprehensive metabolic profiling may potentially help targeting preventive interventions for young asymptomatic individuals at increased risk for type 2 diabetes.
MIR2052HG regulates ERα levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1
Authors: Cairns Junmei , Ingle James N. , Kalari Krishna R. , Shepherd Lois E. , Kubo Michiaki , Goetz Matthew P. , Weinshilboum Richard M. , Wang Liewei
Published: January 2019

Our previous GWAS using the MA.27 aromatase inhibitors (AIs) adjuvant trial identified SNPs in the lncRNA MIR2052HG associated with breast cancer free interval. Here we report that MIR2052HG depletion in breast cancer cells results in a decrease in LMTK3 expression and cell growth. Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter. LMTK3 sustains ERα levels by reducing PKC activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ERα degradation mediated by the PKC/MEK/ERK/RSK1 pathway. MIR2052HG regulated LMTK3 in a SNP- and aromatase inhibitor - dependent fashion: the variant SNP increased EGR1 binding to LMTK3 promoter in response to androstenedione, relative to wild-type genotype, a pattern that can be reversed by aromatase inhibitor treatment. Finally, LMTK3 overexpression abolished the effect of MIR2052HG on PKC activity and ERα levels. These results reveal a direct role of MIR2052HG in LMTK3 regulation and raise the possibility of targeting MIR2052HG or LMTK3 in ERα-positive breast cancer.
Direct medical and non-medical costs of a one-year care pathway for early breast cancer: results of a French multicenter prospective study
Authors: Héquet Delphine , Huchon Cyrille , Soilly Anne-Laure , Asselain Bernard , Berseneff Hélène , Trichot Caroline , Combes Alix , Alves Karine , Nguyen Thuy , Rouzier Roman , Baffert Sandrine
Published: January 2019

Introduction

The organization of health care for breast (BC) constitutes a public health challenge to ensure quality of care, while also controlling expenditure. Few studies have assessed the global care pathway of early BC patients, including a description of direct medical costs and their determinants.

Methods

OPTISOINS01 was a multicenter, prospective, observational study including early BC patients from diagnosis to one-year follow-up. Direct medical costs (in-hospital and out-ofhospital costs, supportive care costs) and direct non-medical costs (transportation and sick leave costs) were calculated by using a cost-of-illness analysis based on a bottom-up approach. Resources consumed were recorded in situ for each patient, using a prospective direct observation method.

Results

Data from 604 patients were analyzed. Median direct medical costs of 1 year of management after diagnosis in operable BC patients were €12,250. Factors independently associated with higher direct medical costs were: diagnosis on the basis of clinical signs, invasive cancer, lymph node involvement and conventional hospitalization for surgery. Median sick leave costs were €8,841 per patient and per year. Chemotherapy was an independent determinant of sick leave costs (€3,687/patient/year without chemotherapy versus €10,706 with chemotherapy). Forty percent (n=242) of patients declared additional personal expenditure of €614/patient/year. No drivers of these costs were identified.

Conclusion

Initial stage of disease and the treatments administered were the main drivers of direct medical costs. Direct non-medical costs essentially consisted of sick leave costs, accounting for one-half of direct medical costs for working patients. Out-of-pocket expenditure had a limited impact on the household.
Absenteeism and indirect costs during the year following the diagnosis of an operable breast cancer
Authors: Ferrier Clement , Thebaut Clémence , Levy Pierre , Baffert Sandrine , Asselain Bernard , Rouzier Roman , Hequet Delphine
Published: January 2019

Introduction

The consequences of disease on work for individual patients as well as the consequences of absenteeism from work are subjects of interest for decision-makers.

Methods

We analyzed duration of absenteeism and related indirect costs for patients with a paid job during the year following diagnosis of early-stage breast cancer in the prospective OPTISOINS01 cohort. A human capital and friction costs approaches were considered for evaluation of lost working days. For this analysis, the friction period was estimated from recent French data. Statistical analysis included simple and multiple linear regression to identify determinants of absenteeism and indirect costs.

Results

93% of patients had at least one period of sick leave, with an average of 2 periods of sick leave and a mean total duration of 186 days. 24% of patients returned to work part-time after an average sick leave of 114 days (i.e. 41 LWD). Estimated indirect costs were €22,722.00 and €7,724.00 per patient, for the human capital and friction cost approaches, respectively. In the multiple linear regression model, factors associated with absenteeism were: invasive tumor (p=.043), mastectomy (p=.038), redo surgery (p=.002), chemotherapy (p=.027), being a manager (p=.025) or a craftsman (p=.005).

Conclusion

Breast cancer is associated with long periods of absenteeism during the year following diagnosis, but almost all patients were able to return to work. Major differences in the results were observed between the friction cost and human capital approaches, highlighting the importance of considering both approaches in such studies.
NanoR: a user-friendly R package to analyze and compare nanopore sequencing data
Authors: Bolognini Davide , Bartalucci Niccolò , Mingrino Alessandra , Vannucchi Alessandro Maria , Magi Alberto
Published: January 2019

MinION and GridION X5 from Oxford Nanopore Technologies are devices for real-time DNA and RNA sequencing. On the one hand, MinION is the only real-time, low cost and portable sequencing device and, thanks to its unique properties, is becoming more and more popular among biologists; on the other, GridION X5, mainly for its costs, is less widespread but highly suitable for researchers with large sequencing projects. Despite the fact that Oxford Nanopore Technologies’ devices have been increasingly used in the last few years, there is a lack of high-performing and user-friendly tools to handle the data outputted by both MinION and GridION X5 platforms. Here we present NanoR, a cross-platform R package designed with the purpose to simplify and improve nanopore data visualization. Indeed, NanoR is built on few functions but overcomes the capabilities of existing tools to extract meaningful informations from MinION sequencing data; in addition, as exclusive features, NanoR can deal with GridION X5 sequencing outputs and allows comparison of both MinION and GridION X5 sequencing data in one command. NanoR is released as free package for R at https://github.com/davidebolo1993/NanoR.
Dynamic Predictive Accuracy of Electrocardiographic Biomarkers of Sudden Cardiac Death within a Survival Framework: The Atherosclerosis Risk in Communities (ARIC) study
Authors: Perez-Alday Erick A. , Bender Aron , Li-Pershing Yin , German David , Mai Tuan , Mukundan Srini V. , Hamilton Christopher , Thomas Jason , Tereshchenko Larisa G.
Published: January 2019

Background

The risk of sudden cardiac death (SCD) is known to be dynamic. However, an accuracy of a dynamic SCD prediction, and “expiration date” of ECG biomarkers is unknown. Our goal was to measure dynamic predictive accuracy of ECG biomarkers of SCD and competing outcomes.

Methods

Atherosclerosis Risk In Community study participants with analyzable digital ECGs were included (n=15,768; 55% female, 73% white, age 54.2±5.8 y). ECGs of 5 follow-up visits were analyzed. Global electrical heterogeneity (GEH) and traditional ECG metrics were measured. Adjudicated SCD served as the primary outcome; non-sudden cardiac death served as competing outcome. Time-dependent area under the (receiver operating characteristic) curve (AUC) analysis was performed to assess prediction accuracy of a continuous biomarker in a period of 3,6,9 months, and 1,2,3,5,10, and 15 years, using survival analysis framework.

Results

Over a median 24.4 y follow-up, there were 581 SCDs (incidence 1.77 (95%CI 1.63-1.92)/1,000 person-years), and 838 nonSCDs [2.55 (95%CI 2.39-2.73)]. Resting heart rate was the strongest (AUC 0.930) short-term (3-month) non-specific SCD predictor, whereas spatial peak QRS-T angle predicted specifically SCD 15 years after ECG recording (AUC 0.719). QRS duration (AUC 0.885) and QTc (AUC 0.711) short-term predicted advanced structural heart disease better than SCD. “Expiration date” for most ECG biomarkers was two years after ECG recording. GEH significantly improved reclassification of SCD risk beyond age, sex, race, diabetes, hypertension, coronary heart disease and stroke.

Conclusion

Short-term predictors of SCD, nonSCD, and biomarkers of long-term SCD risk differed, reflecting differences in transient vs. persistent SCD substrates.
Afferent connections of the primary somatosensory cortex of the mouse for contextual and multisensory processing
Authors: Massé Ian Omer , Blanchet-Godbout Sohen , Bronchti Gilles , Boire Denis
Published: January 2019

Sensory information is conveyed from peripheral receptors through specific thalamic relays to primary areas of the cerebral cortex. Information is then routed to specialized areas for the treatment of specific aspects of the sensory signals and to multisensory associative areas. Information processing in primary sensory cortices is influenced by contextual information from top-down projections of multiple cortical motor and associative areas as well as areas of other sensory modalities and higher order thalamic nuclei. The primary sensory cortices are thus located at the interface of the ascending and descending pathways. The theory of predictive coding implies that the primary areas are the site of comparison between the sensory information expected as a function of the context and the sensory information that comes from the environment. To better understand the anatomical basis of this model of sensory systems we have charted the cortical and subcortical afferent inputs in the ipsilateral and contralateral hemispheres of the primary somatosensory cortex of adult C57Bl/6 mice. Iontophoretic injections of the b-fragment of cholera toxin were performed inside the mystacial caudal barrel field, more rostral barrel field and somatosensory cortex outside the barrel field to test the hypothesis that differences exist between these three parts and to compare their projections to the subnetworks built from the Mouse Connectome Project data. The laminar distribution of retrogradely labeled cell bodies was used to classify the projections as feedback, feedforward or lateral. Layer indices range between −1 and 1, indicating feedback and feedforward connections respectively. The primary somatosensory cortex and the barrel field have afferent connections with somatosensory areas, non-somatosensory primary sensory areas, multisensory, motor, associative, and neuromodulatory areas. The caudal part of the barrel field displays different and more abundant cortical and subcortical connections compared to the rest of the primary somatosensory cortex. Layer indices of cortical projections to the primary somatosensory cortex and the barrel field were mainly negative and very similar for ipsilateral and contralateral projections. These data demonstrate that the primary somatosensory cortex receives sensory and non-sensory information from cortical and subcortical sources.
EvolvingSTEM: A microbial evolution-in-action curriculum that enhances learning of evolutionary biology and biotechnology
Authors: Cooper Vaughn S. , Warren Taylor M. , Matela Abigail M. , Handwork Michael , Scarponi Shani
Published: January 2019

Evolution is a central, unifying theory for all of life science, yet the subject is poorly represented in most secondary-school biology courses, especially in the United States. One challenge to learning evolution is that it is taught as a conceptual, retrospective subject with few tangible outcomes for students. These typical passive learning strategies lead to student disengagement with the material and misunderstanding of evolutionary concepts. To promote greater investment and comprehension, we developed EvolvingSTEM, an inquiry-based laboratory curriculum that demonstrates concepts of natural selection, heredity, and ecological diversity through experimental evolution of a benign bacterium. Students transfer populations ofPseudomonas fluorescensgrowing on plastic beads, which selects for biofilm formation and mutants with new, conspicuous phenotypes. We introduced our curriculum to four introductory high school biology classes alongside their standard curriculum materials and found that students who learned evolution through EvolvingSTEM scored significantly better on a common assessment targeted to Next Generation Science Standards than students taught only the standard curriculum. This latter group subsequently achieved similar scores once they too completed our curriculum. Our work demonstrates that inquiry-based, hands-on experiences with evolving bacterial populations can greatly enhance student learning of evolutionary concepts.
Microbial associations and spatial proximity predict North American moose (Alces alces) gastrointestinal community composition
Authors: Fountain-Jones Nicholas M. , Clark Nicholas J. , Kinsley Amy C. , Carstensen Michelle , Forester James , Johnson Timothy J. , Miller Elizabeth , Moore Seth , Wolf Tiffany M. , Craft Meggan E.
Published: January 2019

Microbial communities are increasingly recognised as crucial for animal health. However, our understanding of how microbial communities are structured across wildlife populations is poor. Mechanisms such as interspecific associations are important in structuring free-living communities, but we still lack an understanding of how important interspecific associations are in structuring gut microbial communities in comparison to other factors such as host characteristics or spatial proximity of hosts.

Here we ask how gut microbial communities are structured in a population of North American moose (Alces alces). We identify key microbial interspecific associations within the moose gut and quantify how important they are relative to key host characteristics, such as body condition, for predicting microbial community composition.

We sampled gut microbial communities from 55 moose in a population experiencing decline due to a myriad of factors, including pathogens and malnutrition. We examined microbial community dynamics in this population utilizing novel graphical network models that can explicitly incorporate spatial information.

We found that interspecific associations were the most important mechanism structuring gut microbial communities in moose and detected both positive and negative associations. Models only accounting for associations between microbes had higher predictive value compared to models including moose sex, evidence of previous pathogen exposure, or body condition. Adding spatial information on moose location further strengthened our model and allowed us to predict microbe occurrences with ∼90% accuracy.

Collectively, our results suggest that microbial interspecific associations coupled with host spatial proximity are vital in shaping infra communities in a large herbivore. In this case, previous pathogen exposure and moose body condition were not as important in predicting gut microbial community composition. The approach applied here can be used to quantify interspecific associations and gain a more nuanced understanding of the spatial and host factors shaping microbial communities in non-model hosts.
Dynamic coordination of the perirhinal cortical neurons supports coherent representations between task epochs
Authors: Ohnuki Tomoya , Osako Yuma , Manabe Hiroyuki , Sakurai Yoshio , Hirokawa Junya
Published: January 2019

Cortical neurons show distinct firing patterns across multiple task-epochs characterized by distinct computational aspects. Recent studies suggest that such distinct patterns underly dynamic population code achieving computational flexibility, whereas neurons in some cortical areas often show coherent firing patterns across epochs. To understand how such coherent single-neuron code contribute to dynamic population code, we analyzed neural responses in the perirhinal cortex (PRC) during cue and reward epochs of a two-alternative forced-choice task. We found that the PRC neurons often encoded the opposite choice-directions between those epochs. By using principal component analysis as population-level analysis, we identified neural subspaces associated with each epoch, which reflected coordinated patterns across the neurons. The cue and reward epochs shared neural dimensions where the choice directions were consistently discriminated. Interestingly, those dimensions were supported by dynamically changing contributions of individual neurons. These results indicated heterogeneity of coherent single-neuron responses in their contribution to population code.
Rapid and extensive karyotype diversification in haploid clinical Candida auris isolates
Authors: Bravo Ruiz Gustavo , Ross Zoe K. , Schelenz Silke , Gow Neil A.R. , Lorenz Alexander
Published: January 2019

Candida auris is a newly emerging pathogenic microbe, having been identified as a medically relevant fungus as recently as 2009. It is the most drug-resistant yeast species known to date and its emergence and population structure are unusual. Because of its recent emergence we are largely ignorant about fundamental aspects of its general biology, life cycle, and population dynamics. Here we report the karyotype variability of 26 C. auris strains representing the four main clades. We demonstrate that all strains are haploid and have a highly plastic karyotype containing five to seven chromosomes, which can undergo marked alterations within a short time-frame when the fungus is put under genotoxic, heat, or osmotic stress. No simple correlation was found between karyotype pattern, drug resistance, and clade affiliation indicating that karyotype heterogeneity is rapidly evolving. As with other Candida species, these marked karyotype differences between isolates are likely to have an important impact on pathogenic traits of C. auris.
Visual signal evolution along complementary color axes in four bird lineages
Authors: Krishnan Anand , Singh Avehi , Tamma Krishnapriya
Published: January 2019

Animal color patterns function in varied behavioral contexts including recognition, camouflage and even thermoregulation. The diversity of visual signals may be constrained by various factors, for example, dietary factors, and the composition of ambient environmental light (sensory drive). How have high-contrast and diverse signals evolved within these constraints? In four bird lineages, we present evidence that plumage colors cluster along a line in tetrachromatic color space. Additionally, we present evidence that this line represents complementary colors, which are defined as opposite sides of a line passing through the achromatic point (putatively for higher chromatic contrast). Finally, we present evidence that interspecific color variation over at least some regions of the body is not constrained by phylogenetic relatedness. Thus, we hypothesize that species-specific plumage patterns within these bird lineages evolve by swapping the distributions of a complementary color pair (or dark and light patches in one group, putatively representing an achromatic complementary axis). The relative role of chromatic and achromatic contrasts in discrimination may depend on the environment that each species inhabits.
The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures
Authors: Girard Benoit , Tuduri Pola , Moreno Maria Paula , Sakkaki Sophie , Barboux Cedric , Bouschet Tristan , Varrault Annie , Vitre Jihane , McCort Isabelle , Dairou Julien , Acher Francine , Fagni Laurent , Marchi Nicola , Perroy Julie , Bertaso Federica
Published: January 2019

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures.

We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazol systemic injection), LSP2-9166 induces an anti-epileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found LSP2-9166 reduced seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti-epileptic drug on established seizures in both models tested.

Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.
Mosaic origin of the eukaryotic kinetochore
Authors: van Hooff Jolien J.E. , Tromer Eelco , Kops Geert J.P.L. , Snel Berend
Published: January 2019

The emergence of eukaryotes from ancient prokaryotic lineages was accompanied by a remarkable increase in cellular complexity. While prokaryotes use simple systems to connect DNA to the segregation machinery during cell division, eukaryotes use a highly complex protein assembly known as the kinetochore. Although conceptually similar, prokaryotic segregation systems and eukaryotic kinetochore proteins share no homology, raising the question of the origins of the latter. Using large-scale gene family reconstruction, sensitive profile-versus-profile homology detection and protein structural comparisons, we here reveal that the kinetochore of the last eukaryotic common ancestor (LECA) consisted of 52 proteins that share deep evolutionary histories with proteins involved in a few prokaryotic processes and a multitude of eukaryotic processes, including ubiquitination, chromatin regulation and flagellar as well as vesicular transport systems. We find that gene duplications played a major role in shaping the kinetochore: roughly half of LECA kinetochore proteins have other kinetochore proteins as closest homologs. Some of these (e.g. subunits of the Mis12 complex) have no detectable homology to any other eukaryotic protein, suggesting they arose as kinetochore-specific proteins de novo before LECA. We propose that the primordial kinetochore evolved from proteins involved in various (pre-)eukaryotic systems as well as novel proteins, after which a subset duplicated to give rise to the complex kinetochore of LECA.
Modeling Primary Fields of TMS Coils with the Fast Multipole Method
Authors: Makarov Sergey N. , de Lara Lucia Navarro , Noetscher Gregory M. , Nummenmaa Aapo
Published: January 2019

In this study, an accurate TMS-coil modeling approach based on conductor’s cross-section representation with many distributed current filaments coupled with an efficient fast multipole method (FMM) accelerator is developed and tested. Uniform (Litz wire) or skin-effect based current distributions are included into consideration. Speed and accuracy estimates as well as two application examples are given, which indicate that this approach is potentially capable of rapid and accurate evaluation of various detailed TMS coil designs and arrays of such coils.

The MATLAB-based wire and CAD mesh generator for the coil geometry is interfaced with the FMM FORTAN program, which is also compiled within the MATLAB shell. No extra MATLAB toolboxes are necessary. The CAD model of the coil can be imported into any other computational software package in STL format. The algorithm is organized in the form of a MATLAB-based toolkit. First, a coil model is generated using a dedicated script. Then, we compute high-resolution 2D contour plots for any component of the electric and/or magnetic field in coronal, sagittal, and transverse planes via FMM. These two scripts may be further augmented with a parametric loop to enable rapid analysis.

Objective

We show how the fast multipole method can be applied to compute primary electric and magnetic fields for detailed TMS coil models
Allele-Specific Expression and High-Throughput Reporter Assay Reveal Functional Variants in Human Brains with Alcohol Use Disorders
Authors: Rao Xi , Thapa Kriti S. , Chen Andy B , Lin Hai , Gao Hongyu , Reiter Jill L , Hargreaves Katherine A. , Ipe Joseph , Lai Dongbing , Xuei Xiaoling , Gu Hongmei , Kapoor Manav , Farris Sean P. , Tischfield Jay , Foroud Tatiana , Goate Alison M. , Skaar Todd C , Mayfield R. Dayne , Edenberg Howard J. , Liu Yunlong
Published: January 2019

Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with alcohol use disorder (AUDs) may cause expression differences, we integrated deep RNA-seq and genome-wide association studies (GWAS) data from four postmortem brain regions of 30 AUDs subjects and 30 controls (social/non-drinkers) and analyzed allele-specific expression (ASE). We identified 90 genes with differential ASE in subjects with AUDs compared to controls. Of these, 61 genes contained 437 single nucleotide polymorphisms (SNPs) in the 3’ untranslated regions (3’UTR) with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that showed affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these are in binding sites of miRNAs and RNA binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE.
Lower-limb rigidity is associated with frequent falls in Parkinson disease
Authors: McKay J. Lucas , Hackney Madeleine. E. , Factor Stewart A. , Ting Lena H.
Published: January 2019

BACKGROUND AND OBJECTIVE:

The role of muscle rigidity as an etiological factor of falls in Parkinson disease (PD) is poorly understood. Our objective was to determine whether lower leg rigidity was differentially associated with frequent falls in PD compared to upper limb, neck, and total rigidity measures. METHODS: We examined associations between UPDRS-III (motor) rigidity subscores and history of monthly or more frequent falls in N=216 individuals with PD (age, 66±10 y; 36% female, disease duration, 7±5 y) with logistic regression. RESULTS: N=35 individuals were frequent fallers. Significant associations were identified between lower limb rigidity and frequent falls (P=0.01) after controlling for age, sex, PD duration, total UPDRS-III score, and presence of FOG. No significant associations (P≥0.14) were identified for total, arm, or neck rigidity. CONCLUSION: Lower limb rigidity is related to frequent falls in people with PD. Further investigation may be warranted into how parkinsonian rigidity could cause falls.

Financial Disclosures/Conflict of Interest concerning the research related to the manuscript: None

Funding:

NIH K25HD086276, R01HD046922, R21HD075612, UL1TR002378, UL1TR000454; Department of Veterans Affairs R&D Service Career Development Awards E7108M and N0870W, Consolidated Anti-Aging Foundation, and the Sartain Lanier Family Foundation.
Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5
Authors: Qiao Xi , Liu Ying , Prada Maria Llamazares , Gupta Abhishekh , Jaiswal Alok , Sharma Mukund , Haikala Heidi , Talvinen Kati , Yetukuri Laxman , Pylvänäinen Joanna W. , Klefström Juha , Kronqvist Pauliina , Meinander Annika , Aittokallio Tero , Hietakangas Ville , Eilers Martin , Westermarck Jukka
Published: January 2019

MYC protein expression has to be tightly controlled to allow for maximal cell proliferation without inducing apoptosis. Here we discover UBR5 as a novel MYC ubiquitin ligase and demonstrate how it functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 effects on MYC protein stability are independent on N-terminal FBW7 degron of MYC. Endogenous UBR5 inhibition induces MYC protein expression and activates MYC target genes. Moreover, UBR5 governs MYC-dependent phenotypes in vivo in Drosophila. In cancer cells, UBR5-mediated MYC protein suppression diminishes cell killing activity of cancer therapeutics. Further, we demonstrate that UBR5 dominates MYC protein expression at the single-cell level in human basal-type breast cancer tissue. Myc and Ubr5 are co-amplified in MYC-driven human cancer types, and UBR5 controls MYC-mediated apoptotic threshold in co-amplified basal type breast cancer cells. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC protein expression in vivo. Clinically, expression of UBR5 may be important for protection of breast cancer cells from drug-induced, and MYC-dependent, apoptosis.
Effects of enucleation on the direct reciprocal corticocortical connections between primary visual and somatosensory cortices of the mouse
Authors: Massé Ian Omer , Bronchti Gilles , Boire Denis
Published: January 2019

Multisensory convergence is present in the cerebral cortex even at the initial stages of processing in the primary and low-level sensory cortices. Direct connections between primary sensory cortices are a particular feature of rodent cortical connectivity. Our previous studies have shown asymmetric projections between the primary visual and somatosensory cortices in mice. Binocular enucleation produces a relative reduction of the projections from the somatosensory cortex to the visual cortex in mice. The purpose of this study is to compare the direct reciprocal cross-modal connections between the primary visual (V1) and somatosensory (S1) cortices in intact and enucleated C57Bl/6 mice, and to determine quantitative differences in the proportion and laminar distribution of neurons and terminals in these projections. CTB labeled neurons were used to estimate the relative importance of projections between V1 and S1, and their laminar distribution used to classify them as feedback, feedforward or lateral projections. The size of axonal swellings was measured and frequency distribution determined for each cortical layer. Axon diameters were also sampled in these connections. Injections in V1 resulted in a reduced proportion of labeled cells in S1 of enucleated mice. There was a relative decrease of the projection from the somatosensory cortex to the visual cortex in enucleated mice due to a greater relative reduction of supragranular layers neurons. Enucleation otherwise had no effect on the connectivity of the somatosensory cortex with other motor and somatosensory cortices. In the projection from the visual to the somatosensory cortex in enucleated mice, the size of axonal swellings was reduced in all layers. Conversely, in the projection from the somatosensory cortex to the visual cortex, some larger swellings appeared in the supragranular layers. This shows pathway and laminar specific changes in cortical circuitry following loss of sensory afferent activity that results in changes in the relationship between visual and somatosensory cortices in the enucleated mice.
Complex pleiotropic genetic architecture of evolved heat stress and oxidative stress resistance in the nematodeCaenorhabditis remanei
Authors: O’Connor Christine H. , Sikkink Kristin L. , Nelson Thomas C. , Fierst Janna L. , Cresko William A. , Phillips Patrick C.
Published: January 2019

The adaptation of complex organisms to changing environments has been a central question in evolutionary quantitative genetics since its inception. The structure of the genotype-phenotype maps is critical because pleiotropic effects can generate widespread correlated responses to selection and potentially restrict the extent of evolutionary change. In this study we use experimental evolution to dissect the genetic architecture of natural variation for acute heat stress and oxidative stress response in the nematodeCaenorhabiditis remanei. Previous work in the classic model nematodeC. eleganshas found that abiotic stress response is controlled by a handful of genes of major effect and that mutations in any one of these genes can have widespread pleiotropic effects on multiple stress response traits. Here, we find that acute heat stress response and acute oxidative response inC. remaneiare polygenic, complex traits, with hundreds of genomic regions responding to selection. In contrast to expectation from mutation studies, we find that evolved acute heat stress and acute oxidative stress response for the most part display independent genetic bases. This lack of correlation is reflected at the levels of phenotype, gene expression, and in the genomic response to selection. Thus, while these findings support the general view that rapid adaptation can be generated by changes at hundreds to thousands of sites in the genome, the architecture of segregating variation is likely to be strongly parcellated by the pleiotropic structure of the underlying genetic networks.
Differential gene expression in brain and liver tissue of Wistar rats after rapid eye movement sleep deprivation
Authors: Pandey Atul , Oliver Ryan , Kar Santosh K
Published: January 2019

Sleep is essential for the survival of most living beings. Numerous researchers have identified a series of genes that are thought to regulate “sleep-state” or the “deprived state”. As sleep has significant effect on physiology, we believe that lack of sleep or particularly REM sleep for a prolonged period would have a profound impact on various body tissues. Therefore, using microarray method, we sought to determine which genes and processes are affected in the brain and liver of rats following 9 days of REM sleep deprivation. Our findings showed that REM sleep deprivation affected a total of 652 genes in the brain and 426 genes in the liver. Only 23 genes were affected commonly, 10 oppositely and 13 similarly across brain and liver tissue. Our results suggest that 9-day REM sleep deprivation differentially affects genes and processes in the brain and liver of rats.

Highlights of the study

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Gene expression profile of brain and liver tissues of rats was analyzed using microarray technique following 9 days of REM Sleep deprivation.

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Many of the genes involved in essential physiological processes, such as protein synthesis and neuronal metabolism are affected differently in the brain and liver tissue of rats after 9-day REM sleep deprivation.
Preoptic galanin neuron activation is specific to courtship reproductive tactic in fish with two male morphs
Authors: Tripp Joel A. , Salas-Allende Isabella , Makowski Andrea , Bass Andrew H.
Published: January 2019

Species exhibiting alternative reproductive tactics (ARTs) provide ideal models for investigating neural mechanisms underlying robust and consistent differences in social behavioral phenotypes between individuals within a single sex. Using phospho-S6 protein (pS6), a neural activity marker, we investigate the activation of galanin-expressing neurons in the preoptic area-anterior hypothalamus (POA-AH) during ARTs in midshipman fish (Porichthys notatus) that have two adult male morphs: type I’s that reproduce using an acoustic-dependent courtship tactic or a cuckolding tactic, and type II’s that only cuckold. The proportion of pS6-labelled galanin neurons increases during mating by courting type I males, but not cuckolders of either male morph or females, and is not explained by vocalization, eggs in the nest, or cuckolders present during mating. These differences within the same behavioral context indicate a male phenotype-specific role for galanin neurons in mating interactions, providing the most direct evidence to date for the role of a specific neuronal population in the differential activation of one mating behavior over the other in species exhibiting ARTs. More broadly, together with their known role in mammalian mating, the results suggest a deep-rooted, phylogenetically shared function for POA-AH galanin neurons in reproductive behavior. As such, these findings also provide new insights into the evolutionary relationship between POA-AH populations involved in social behavior regulation in teleosts, the most species-rich vertebrate group, with those in the more highly differentiated POA-AH of mammals.

Significance Statement

Galanin-expressing neurons in the preoptic area-anterior hypothalamus (POA-AH) are associated with mating and parental care in mammals. Here, we show that POA-AH galanin neurons are also active in a teleost fish during mating in a social context specific to one of two male morphs of a species with alternative reproductive tactics (ARTs). Together, the results suggest a key role for galanin-expressing neurons in the performance of reproductive-related social behaviors that is shared between distantly related vertebrate lineages and for galanin neuron activation in the evolution of ARTs. The results also help to clarify the relationship between molecularly-defined populations in the teleost POA-AH with the more highly differentiated mammalian POA-AH.
Frequency dependent responses of neuronal models to oscillatory inputs in current versus voltage clamp
Authors: Rotstein Horacio G. , Nadim Farzan
Published: January 2019

Action potential generation in neuron depends on a membrane potential threshold, and therefore on how subthreshold inputs influence this voltage. In oscillatory networks, for example, many neuron types have been shown to produce membrane potential (Vm) resonance: a maximum subthreshold response at a nonzero frequency. Resonance is usually measured by recording Vm in response to a sinusoidal current (Iapp), applied at different frequencies (f), an experimental setting known as current clamp (I-clamp). Several recent studies, however, use the voltage clamp (V-clamp) method to control Vm with a sinusoidal input at different frequencies (Vapp(f)) and measure the total membrane current (Im). The two methods obey systems of differential equations of different dimensionality and, while I-clamp provides a measure of electrical impedance (Z(f) = Vm(f)/Iapp(f)), V-clamp measures admittance (Y (f) = Im(f)/Vapp(f)). We analyze the relationship between these two measurement techniques. We show that, despite different dimensionality, in linear systems the two measures are equivalent: Z = Y−1. However, nonlinear model neurons produce different values for Z and Y−1. In particular, nonlinearities in the voltage equation produce a much larger difference between these two quantities than those in equations of recovery variables that describe activation and inactivation kinetics. Neurons are inherently nonlinear and, notably, with ionic currents that amplify resonance, the voltage clamp technique severely underestimates the current clamp response. We demonstrate this difference experimentally using the PD neurons in the crab stomatogastric ganglion. These findings are instructive for researchers who explore cellular mechanisms of neuronal oscillations.
Competing interactions modulate the activity of Sgs1 during DNA end resection
Authors: Kasaciunaite Kristina , Fettes Fergus , Levikova Maryna , Daldrop Peter , Cejka Petr , Seidel Ralf
Published: January 2019

DNA double-strand break repair by homologous recombination employs long-range resection of the 5’ DNA ends at the break points. In Saccharomyces cerevisiae, this process can be performed by the RecQ helicase Sgs1 and the helicase-nuclease Dna2. Though functional interplay has been shown, it remains unclear whether and how the proteins cooperate on the molecular level. Here, we resolved the dynamics of DNA unwinding by Sgs1 at the single molecule level and investigated its regulation by Dna2, the single-stranded DNA binding protein RPA and the Top3-Rmi1 complex. We found that Dna2 modulates the velocity of Sgs1, indicating that during end resection the proteins form a physical complex and couple their activities. Sgs1 unwinds DNA and feeds single-stranded DNA to Dna2 for degradation. RPA is found to regulate the processivity and the affinity of Sgs1 to the DNA fork, while Top3-Rmi1 modulated the velocity of Sgs1. We think that the differential regulation of the Sgs1 activity by its protein partners is important to allow diverse cellular functions of Sgs1 during the maintenance of genome stability.
Sensorimotor functional connectivity in unilateral cerebral palsy: influence of corticospinal tract wiring pattern and clinical correlates
Authors: Simon-Martinez Cristina , Jaspers Ellen , Alaerts Kaat , Ortibus Els , Balsters Joshua , Mailleux Lisa , Blommaert Jeroen , Sleurs Charlotte , Klingels Katrijn , Amant Frédéric , Uyttebroeck Anne , Wenderoth Nicole , Feys Hilde
Published: January 2019

In children with unilateral cerebral palsy (uCP), the corticospinal tract (CST) wiring patterns may differ (contralateral, ipsilateral or bilateral), partially determining motor deficits. However, the impact of such CST wiring on functional connectivity remains unknown. Here, we explored differences in functional connectivity of the resting-state sensorimotor network in 26 uCP with periventricular white matter lesions (mean age (SD): 12.87m (±4.5), CST wiring: 9 contralateral, 9 ipsilateral, 6 bilateral) compared to 60 healthy controls (mean age (SD): 14.54 (±4.8)), and between CST wiring patterns. Functional connectivity from each M1 to three bilateral sensorimotor regions of interest (primary sensory cortex, dorsal and ventral premotor cortex) and the supplementary motor area was compared between groups (healthy controls vs. uCP; and healthy controls vs. each CST wiring group). Results from the seed-to-voxel analyses from bilateral M1 were compared between groups. Additionally, relations with upper limb motor deficits were explored. Aberrant sensorimotor functional connectivity seemed to be CST-dependent rather than specific from all the uCP population: in the dominant hemisphere, the contralateral CST group showed increased connectivity between M1 and premotor cortices, whereas the bilateral CST group showed higher connectivity between M1 and somatosensory association areas. These results suggest that functional connectivity of the sensorimotor network is CST wiring-dependent, although the impact on upper limb function remains unclear.