bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis and experimental verification of a single‐switch high‐voltage gain ZCS DC–DC converter
Authors: Hassan Waqas , Lu Dylan Dah‐Chuan , Xiao Weidong
Published: May 2019

This study proposes and analyses the integration of soft‐switching technique with a single switch, non‐isolated, coupled inductor DC–DC converter to achieve high efficiency and high step‐up conversion ratio. The topology optimally integrates the coupled inductor and soft‐switching technique using a parallel LC resonant tank circuit to maintain zero‐current switching (ZCS) for on/off switching. The leakage inductance of the coupled inductor alleviates the reverse‐recovery issue of diodes, and diodes can operate under ZCS condition. Moreover, the converter operates in a lower frequency range due to high step‐up voltage gain. The principle of operation and steady‐state analyses of the proposed converter are presented. A prototype validates the theoretical analysis and demonstrates a higher peak efficiency of 96.43% than the corresponding hard‐switched converter.
Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
Authors: Taylor D. Leland , Jackson Anne U. , Narisu Narisu , Hemani Gibran , Erdos Michael R. , Chines Peter S. , Swift Amy , Idol Jackie , Didion John P. , Welch Ryan P. , Kinnunen Leena , Saramies Jouko , Lakka Timo A. , Laakso Markku , Tuomilehto Jaakko , Parker Stephen C. J. , Koistinen Heikki A. , Davey Smith George , Boehnke Michael , Scott Laura J. , Birney Ewan , Collins Francis S.
Published: May 2019

We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased
RXRA
muscle expression may decrease lean tissue mass.
Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization
Authors: Chung Jean K. , Nocka Laura M. , Decker Aubrianna , Wang Qi , Kadlecek Theresa A. , Weiss Arthur , Kuriyan John , Groves Jay T.
Published: May 2019

Significance

Bruton’s tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase critical for B cell signal transduction. While it has been known that its activation requires localization to the plasma membrane by lipid second messenger phosphatidylinositol (3–5)-triphosphate (PIP
3
), the structural basis for activation had been unclear. In this work, the interaction between the membrane-binding domain of Btk and PIP
3
was studied in a reconstituted membrane system. Quantitative investigations through molecular diffusion and adsorption kinetics show that Btk undergoes dimerization-mediated activation in a PIP
3
density-dependent manner, providing a ligand-counting mechanism with a sharp sensitivity to signal strength. This mechanism is not present in related kinases in T cells, Tec and Itk, highlighting the differences in B and T cell regulations.
Subthalamic neuromodulation improves short-term motor learning in Parkinson’s disease
Authors: de Almeida Marcelino Ana Luísa , Horn Andreas , Krause Patricia , Kühn Andrea A , Neumann Wolf-Julian
Published: May 2019

The basal ganglia and cerebellum are implicated in both motor learning and Parkinson’s disease. Deep brain stimulation (DBS) is an established treatment for advanced Parkinson’s disease that leads to motor and non-motor effects by modulating specific neural pathways. Recently, a disynaptic projection from the subthalamic nucleus (STN) to cerebellar hemispheres was discovered. To investigate the functional significance of this pathway in motor learning, short-term improvement in motor execution in 20 patients with Parkinson’s disease on and off STN-DBS and 20 age-matched healthy controls was studied in a visuomotor task combined with whole-brain connectomics. Motor learning was impaired in Parkinson’s disease off stimulation but was partially restored through DBS. Connectivity between active DBS contacts and a distributed network of brain regions correlated with improvement in motor learning. Region of interest analysis revealed connectivity from active contact to cerebellar hemisphere ipsilateral to hand movement as the strongest predictor for change in motor learning. Peak predictive voxels in the cerebellum localized to Crus II of lobule VII, which also showed higher STN than motor cortex connectivity, suggestive of a connection surpassing motor cortex. Our findings provide new insight into the circuit nature of Parkinson’s disease and the distributed network effects of DBS in motor learning.
Nymph, Scarab, Butterfly: Figures of the Dancer in Mérimée, Flaubert and Proust
Authors: MacKenzie Robin
Published: May 2019

This article examines dance episodes from three works of French fiction written between 1860 and 1920: the roussalka dance from Mérimée’s Lokis, Salomé’s performance in Flaubert’s Hérodias, and the description of an unnamed ballet dancer in Proust’s Le Côté de Guermantes. The texts, in contrasting ways, explore networks of power and desire, as well as the relationship between the aesthetic sphere and the world of social conventions and interactions, thus reflecting the thematic significance of dance in the literary culture of the period. It would be hard to justify constructing a grand narrative that maps the history of dance on to that of its literary representations on the basis of three texts; nevertheless, in the interplay of narrative and metaphor and the portrayal of the dancer’s multiple personae, we can find traces of some major shifts in the evolution of dance from the romantic ballet of the mid-nineteenth century to the coming of modernism at the start of the twentieth.
The Safety, Tolerability, and Pharmacokinetics Profile of BT-11, an Oral, Gut-Restricted Lanthionine Synthetase C-Like 2 Agonist Investigational New Drug for Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial
Authors: Leber Andrew , Hontecillas Raquel , Zoccoli-Rodriguez Victoria , Colombel Jean-Frederic , Chauhan Jyoti , Ehrich Marion , Farinola Nicholas , Bassaganya-Riera Josep
Published: May 2019

BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematology, or urinalysis as compared with placebo. Mean fecal concentrations of BT-11 increased linearly with increasing oral doses, with 2.39 mg/g at 7.7 mg/kg on day 7 of the multiple ascending dose (MAD). Analysis of plasma pharmacokinetics indicates that maximum systemic concentrations are approximately 1/6000th of observed concentrations in feces and the distal gastrointestinal tract. Fecal calprotectin levels were lower in BT-11 treated groups as compared to placebo. BT-11 significantly decreases interferon gamma positive (IFNγ+) and tumor necrosis factor alpha positive (TNFα+) cluster of differentiation 4 positive (CD4+) T cells and increases forkhead box P3 positive (FOXP3+) CD4+ T cells in colonic lamina propria mononuclear cells from patients with CD and patients with UC at concentrations of 0.01 µM when treated ex vivo. BT-11 treatment is well-tolerated with no dose-limiting toxicities up to daily oral doses of 100 mg/kg (16 tablets); whereas the efficacious dose is a single tablet (8 mg/kg). Phase II studies in CD and UC patients are ongoing.
Data mining on YouTube reveals fisher group-specific harvesting patterns and social engagement in recreational anglers and spearfishers
Authors: Sbragaglia Valerio , Correia Ricardo A , Coco Salvatore , Arlinghaus Robert
Published: May 2019

We applied data mining on YouTube videos to better understand recreational fisheries targeting common dentex (Dentex dentex), an iconic species of Mediterranean fisheries. In Italy alone, from 2010 to 2016 spearfishers posted 1051 videos compared to 692 videos posted by anglers. The upload pattern of spearfishing videos followed a seasonal pattern with peaks in July, a trend not found for anglers. The average mass of the fish declared in angling videos (6.4 kg) was significantly larger than the one in spearfishing videos (4.5 kg). Videos posted by spearfishers received significantly more likes and comments than those posted by anglers. Content analysis suggested that the differences in engagement can be related to appreciation of successful spearfishers necessitating relevant personal qualities for catching D. dentex. We also found that the mass of the fish positively predicted social engagement as well as the degree of positive evaluation only in spearfishing videos. This could be caused by the generally smaller odds of catching large D. dentex by spearfishing. Our case study demonstrates that data mining on YouTube can be a powerful tool to provide complementary data on controversial and data-poor aspects of recreational fisheries and contribute to understanding the social dimensions of recreational fishers.
Description, evaluation, and validation of the Teagasc Pig Production Model1
Authors: Calderón Díaz Julia Adriana , Shalloo Laurence , Niemi Jarkko K , Kyriazakis Ilias , McKeon Michael , McCutcheon Gerard , Bohan Alan , Manzanilla Edgar G
Published: May 2019

The Teagasc Pig Production Model (TPPM), a stochastic simulation model of a farrow-to-finish pig farm, was developed to investigate effects of changes in production systems on farm profitability. The model simulates, on a weekly basis, the annual production of a farm. Biological [e.g., herd size, number of litters/sow/year, and mortality rates (%)], physical (e.g., infrastructure), and technical (e.g., feeding practices) variables and their associated costs are included as components of the model. These inputs are used to calculate physical (e.g., feed usage and number of pigs slaughtered) and financial (e.g., annual cash flow, profit and loss account, and balance sheet) outputs. The model was validated using the Delphi method and by comparing the TPPM outputs to data recorded on 20 Irish pig farms through the Teagasc e-Profit monitor system and with complete receipts for the year 2016. Results showed that the TPPM closely simulates physical and financial performance of pig farms indicating that the TPPM can be used with confidence to study pig production systems under Irish conditions. Model applicability was demonstrated by investigating the impact of 2 changes in technical performance: 1) building of extra accommodation to increase body weight (BW) at sale by 15 kg (EXTRA ROOM) and 2) a change in feeding practices by providing finisher feed from 28 kg of BW (EARLY FINISHER) compared with over 38 kg of BW. In both scenarios, the same biological parameters were used. Mortality rates, feed ingredients costs, and price per kg of meat produced were included as stochastic variables with the input distributions derived based on historical data simulated using Monte Carlo sampling using the Microsoft Excel add-in @Risk. Annual mean net profit was €198,101 (90% confidence interval [CI]: €119,606–€275,539) for the TPPM base farm, €337,078 (90% CI: €246,320–€426,809) for the EXTRA ROOM, and €225,598 (90% CI: €146,685–€303,590) for the EARLY FINISHER. EXTRA ROOM was associated with higher costs and required higher income to cover the additional costs. The 90% CI of the EARLY FINISHER was similar to the TPPM base farm while the EXTRA ROOM scenario resulted in a wider confidence interval, suggesting that a change in feeding practices could be a better option for farmers looking to improve profit with minimum investment. Thus, the TPPM could be used to facilitate decision making in farrow-to-finish pig farms.
On the Benefits of Set-Asides
Authors: Jehiel Philippe , Lamy Laurent
Published: May 2019

Set-aside programs that consist in forbidding access to specific participants are commonly used in procurement auctions. We show that when the set of potential participants is composed of an incumbent (whose entry costs are already sunk) and of entrants who show up endogenously (in such a way that their expected rents are fixed by outside options), then it is always beneficial for revenues to exclude the incumbent in the Vickrey auction. This exclusion principle is generalized to dominant-strategy auctions that favor the incumbent in the sense that the incumbent would always get the good when valuing it most. By contrast, set-asides are not desirable if the incumbent’s payoff is included in the seller’s objective in the Vickrey auction, and more generally it is detrimental to exclude a bidder that is not favored.
Oral Complications of Chronic Graft-Versus-Host Disease
Authors: Fall-Dickson Jane M , Pavletic Steven Z , Mays Jacqueline W , Schubert Mark M
Published: May 2019

The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented.
Principles of synthetic biology: a MOOC for an emerging field
Authors: Anderson Daniel A , Jones Ross D , Arkin Adam P , Weiss Ron
Published: May 2019

Synthetic biology requires students and scientists to draw upon knowledge and expertise from many disciplines. While this diversity is one of the field’s primary strengths, it also makes it challenging for newcomers to acquire the background knowledge necessary to thrive. To address this gap, we developed a course that provides a structured approach to learning the biological principles and theoretical underpinnings of synthetic biology. Our course, Principles of Synthetic Biology (PoSB), was released on the massively open online course platform edX in 2016. PoSB seeks to teach synthetic biology through five key fundamentals: (i) parts and layers of abstraction, (ii) biomolecular modeling, (iii) digital logic abstraction, (iv) circuit design principles and (v) extended circuit modalities. In this article, we describe the five fundamentals, our formulation of the course, and impact and metrics data from two runs of the course through the edX platform.
Sodium interception by xylem parenchyma and chloride recirculation in phloem may augment exclusion in the salt tolerant Pistacia genus: context for salinity studies on tree crops
Authors: Godfrey Jessie M , Ferguson Louise , Sanden Blake L , Tixier Aude , Sperling Or , Grattan Steve R , Zwieniecki Maciej A
Published: May 2019

Working in tandem with root exclusion, stems may provide salt-tolerant woody perennials with some additional capacity to restrict sodium (Na) and chloride (Cl) accumulation in leaves. The Pistacia genus, falling at the nexus of salt tolerance and human intervention, provided an ideal set of organisms for studying the influences of both variable root exclusion and potentially variable discontinuities at the bud union on stem processes. In three experiments covering a wide range of salt concentrations (0 to 150 mM NaCl) and tree ages (1, 2 and 10 years) as well as nine rootstock-scion combinations we show that proportional exclusion of both Na and Cl reached up to ~85% efficacy, but efficacy varied by both rootstock and budding treatment. Effective Na exclusion was augmented by significant retrieval of Na from the xylem sap, as evidenced by declines in the Na concentrations of both sap and wood tissue along the transpiration stream. However, while we observed little to no differences between the concentrations of the two ions in leaves, analogous declines in sap concentrations of Cl were not observed. We conclude that some parallel but separate mechanism must be acting on Cl to provide leaf protection from toxicity specific to this ion and suggest that this mechanism is recirculation of Cl in the phloem. The presented findings underline the importance of holistic assessments of salt tolerance in woody perennials. In particular, greater emphasis might be placed on the dynamics of salt sequestration in the significant storage volumes offered by the stems of woody perennials and on the potential for phloem discontinuity introduced with a bud/graft union.
Lassa Virus in the Host RodentMastomys Natalensiswithin Urban Areas of N’zerekore, Guinea
Authors: Karan LS , Makenov MT , Korneev MG , Sacko N , Boumbaly S , Bayandin RB , Gladysheva AV , Kourouma K , Toure AH , Kartashov MYu , Shipovalov AV , Porshakov AM , Koulibaly M , Boiro MY
Published: May 2019

Lassa virus is the causative agent of a dangerous zoonotic disease distributed in West Africa. A primary reservoir host of Lassa virus isMastomys natalensis. These mice associate closely with humans and are commonly found in villages. Consequently, previous studies of Lassa virus have focused on rural areas. The prevalence of the virus in large cities has not been studied.

We conducted a study in N’Zerekore city, which has a population of approximately 300,000 residents. Small mammals were captured during a pilot study in May, and the main study was performed in August 2018. Based on the pilot study, we designed and implemented a stratified random sample to investigate the prevalence of Lassa virus amongM. natalensisin N’Zerekore. The total sampling efforts consisted of 45 and 985 trapping nights in May and August, respectively. Samples of rodent tissues were screened for Lassa virus by RT-PCR.

In May, we trapped 20 rodents, including 19M. natalensis. Viral RNA was detected in 18M. natalensis. In August, 149 small mammals were captured, including 43M. natalensis. The prevalence of Lassa virus amongM. natalensisin N’Zerekore was 23.3% (CI 95%: 11.8–38.6%). Sequencing showed that the isolates belonged to lineage IV. We detected four Lassa virus hotspots located in different parts of the city. The largest Lassa virus hotspot was found in the neighborhood of the central market, which suggests that the virus was originally introduced into the city through the market.
Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways
Authors: Foo Jerome C. , Trautmann Nina , Sticht Carsten , Treutlein Jens , Frank Josef , Streit Fabian , Witt Stephanie H. , De La Torre Carolina , von Heydendorff Steffen Conrad , Sirignano Lea , Chen Junfang , Müller-Myhsok Bertram , Meyer-Lindenberg Andreas , Witt Christian C. , Gilles Maria , Deuschle Michael , Rietschel Marcella
Published: May 2019

Background

Therapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic ‘clocks’ and that SD functions through ‘resetting’ dysregulated genes; additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression.

Methods

Patients (N=78) and controls (N=15) underwent SD, with blood taken at the same time of day before, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted.

Results

Circadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD; in non-responders, little response was observed.

Conclusions

Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level.
Assessing nasal obstruction with the nasal acoustic device: a pilot study on distinguishing between subjects with and without chronic rhinosinusitis
Authors: Li Chia-Hung , Tan Calvin , Whitcroft Katherine L. , Andrews Peter , Leung Terence S.
Published: May 2019

This article aims to demonstrate the concept and potential of a novel diagnostic device – the nasal acoustic device (NAD), which captures the nasal breathing sounds over the ala on both sides of the nose. Using the newly defined inspiratory nasal acoustic score (INA score), the unique characteristics of the nasal breathing sounds can be quantified and used for diagnostic purposes.

In this pilot study, the NAD was compared with the well-established nasal inspiratory peak flow meter (NIPF) to try to distinguish between subjects with and without chronic rhinosinusitis (CRS). Measurements were made before and after nasal decongestants, which were applied to eliminate the nasal cycle. Patients were divided into two groups based on the presence or absence of CRS, irrespective of other pathological conditions being present.

Based on the post-decongestant measurements, the sensitivity/specificity in distinguishing subjects who have CRS (n=11) from subjects who do not (n=29; of whom 13 were controls) were 70%/66% for the NIPF and 82%/79% for the NAD. The non-CRS groups showed statistically significant changes after decongestant for both methods, but the CRS group did not. The results firstly demonstrated that the CRS subjects in this cohort tended to be less responsive to decongestant and therefore the post-decongestant NIPF measurements provided a certain degree of diagnostic value in identifying CRS subjects, but it would appear the NAD better captured the unique sounds associated with CRS, providing a superior diagnostic capability. This study also demonstrates that the NAD can measure the improvement in the nasal airway following treatment effect.
Inverse regulation of secretion and inflammation in human airway gland serous cells by neuropeptides upregulated in allergy and asthma
Authors: McMahon Derek B. , Kohanski Michael A. , Tong Charles C.L. , Papagiannopoulos Peter , Adappa Nithin D. , Palmer James N. , Lee Robert J.
Published: May 2019

Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways from the nose down to small bronchi. We tested if serous cells from human nasal turbinate glands secrete bicarbonate (HCO3−), important for mucus polymerization, during stimulation with the cAMP-elevating agonist vasoactive intestinal peptide (VIP) and if this requires CFTR. Isoalted serous cells stimulated with VIP exhibited a ~20% cAMP-dependent decrease in cell volume and a ~0.15 unit decrease in intracellular pH (pHi), reflecting activation of Cl−and HCO3−secretion, respectively. Pharmacology, ion substitution, and studies using cells from CF patients suggest serous cell HCO3−secretion is mediated by conductive efflux directly through CFTR. Interestingly, we found that neuropeptide Y (NPY) reduced VIP-evoked secretion by blunting cAMP increases and reducing CFTR activation through Gi-coupled NPY1R. Culture of primary gland serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO3−secretion. Moreover, VIP enhanced secretion of antimicrobial peptides and antimicrobial efficacy of gland secretions while NPY reduced antimicrobial secretions. In contrast, NPY enhanced the release of cytokines during inflammatory stimuli while VIP reduced cytokine release through a mechanism requiring CFTR conductance. As levels of VIP and NPY are up-regulated in disease like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control airway mucus rheology and inflammatory responses through gland serous cells.
Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma
Authors: Shrestha Raunak , Nabavi Noushin , Volik Stanislav , Anderson Shawn , Haegert Anne , McConeghy Brian , Brahmbhatt Sonal , Bell Robert H. , Bihan Stephane Le , Wang Yuzhuo , Collins Colin C. , Churg Andrew
Published: May 2019

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process, and if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPM of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C>A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked alterations involving BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 that are frequently altered in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas, and based on observed mutations do not appear to be precursors of malignant mesotheliomas.
A new Bayesian methodology for nonlinear model calibration in Computational Systems Biology
Authors: Bianconi Fortunato , Tomassoni Lorenzo , Antonini Chiara , Valigi Paolo
Published: May 2019

Computational modeling is a common tool to quantitatively describe biological processes. However, most model parameters are usually unknown because they cannot be directly measured. Therefore, a key issue in Systems Biology is model calibration, i.e. estimate parameters from experimental data. Existing methodologies for parameter estimation are divided in two classes: frequentist and Bayesian methods. The first ones optimize a cost function while the second ones estimate the parameter posterior distribution through different sampling techniques. Here, we present an innovative Bayesian method, called Conditional Robust Calibration (CRC), for nonlinear model calibration and robustness analysis using omics data. CRC is an iterative algorithm based on the sampling of a proposal distribution and on the definition of multiple objective functions, one for each observable. CRC estimates the probability density function (pdf) of parameters conditioned to the experimental measures and it performs a robustness analysis, quantifying how much each parameter influences the observables behavior. We apply CRC to three Ordinary Differential Equations (ODE) models to test its performances compared to the other state of the art approaches, namely Profile Likelihood (PL), Approximate Bayesian Computation Sequential Monte Carlo (ABC-SMC) and Delayed Rejection Adaptive Metropolis (DRAM). Compared with these methods, CRC finds a robust solution with a reduced computational cost. CRC is developed as a set of Matlab functions (version R2018), whose fundamental source code is freely available at https://github.com/fortunatobianconi/CRC.
A comparative assessment of adult mosquito trapping methods to estimate spatial patterns of abundance and community composition in southern Africa
Authors: Gorsich Erin E. , Beechler Brianna R. , van Bodegom Peter M. , Govender Danny , Guarido Milehna M. , Venter Marietjie , Schrama Maarten
Published: May 2019

Background

Assessing adult mosquito populations is an important component of disease surveillance programs and ecosystem health assessments. Inference from adult trapping datasets involves comparing populations across space and time, but comparisons based on different trapping methods may be biased if traps have different efficiencies or sample different subsets of the mosquito community.

Methods

We compared four widely-used trapping methods for adult mosquito data collection in Kruger National Park (KNP), South Africa: Centers for Disease Control miniature light trap (CDC), Biogents Sentinel trap (BG), Biogents gravid Aedes trap (GAT) and a net trap. We quantified how trap choice and sampling effort influence inferences on the regional distribution of mosquito abundance, richness and community composition.

Results

The CDC and net traps together collected 96% (47% and 49% individually) of the 955 female mosquitoes sampled and 100% (85% and 78% individually) of the 40 species or species complexes identified. The CDC and net trap also identified similar regional patterns of community composition. However, inference on the regional patterns of abundance differed between these traps because mosquito abundance in the net trap was influenced by variation in weather conditions. The BG and GAT traps collected significantly fewer mosquitoes, limiting regional comparisons of abundance and community composition.

Conclusions

This study represents the first systematic assessment of trapping methods in natural savanna ecosystems in southern Africa. We recommend the CDC trap or the net trap for future monitoring and surveillance programs.
Molecular Expression Profiles of Morphologically Defined Hippocampal Neuron Types: Empirical Evidence and Relational Inferences
Authors: White Charise M. , Rees Christopher L. , Wheeler Diek W. , Hamilton David J. , Ascoli Giorgio A.
Published: May 2019

Gene and protein expressions are key determinants of cellular function. Neurons are the building blocks of brain circuits, yet the relationship between their molecular identity and the spatial distribution of their dendritic inputs and axonal outputs remain incompletely understood. The open-source knowledge base Hippocampome.org amasses such transcriptomic data from the scientific literature for morphologically defined neuron types in the rodent hippocampal formation: dentate gyrus (DG), CA3, CA2, CA1, subiculum (SUB), and entorhinal cortex (EC). Positive, negative, or mixed expression reports were initially obtained from published articles directly connecting molecular evidence to neurons with known axonal and dendritic patterns across hippocampal layers. Here, we supplement this information by collating, formalizing, and leveraging relational expression inferences (REIs) that link a gene or protein expression or lack thereof to that of another molecule or to an anatomical location. With these additional interpretations, we freely release online a comprehensive human- and machine-readable molecular profile for the more than 100 neuron types in Hippocampome.org. Analysis of these data ascertains the ability to distinguish unequivocally most neuron types in each of the major subdivisions of the hippocampus based on currently known biochemical markers. Moreover, grouping neuron types by expression similarity reveals eight super-families characterized by a few defining molecules.

Significance Statement

The molecular composition of cells underlies their structure, activity, and function. Neurons are arguably the most diverse cell types with their characteristic tree-like shapes mediating synaptic communication throughout the brain. Biochemical marker data are available online for hundreds of morphologically identified neuron types in the mammalian hippocampus, including expression of calcium-binding proteins, receptors, and enzymes. Here, we augment this evidence by systematically applying logical rules empirically derived from the published literature (e.g. “presence of molecule X implies lack of molecule Y”). The resulting substantially expanded expression profiles provide nearly unique molecular identities for most known hippocampal neuron types while revealing previously unrecognized genetic similarities across anatomical regions and morphological phenotypes.
HIPPIE2: a method for fine-scale identification of physically interacting chromatin regions
Authors: Kuksa Pavel P. , Amlie-Wolf Alexandre , Hwang Yih-Chii , Valladares Otto , Gregory Brian D. , Wang Li-San
Published: May 2019

Most regulatory chromatin interactions are mediated by various transcription factors (TFs) and involve physically-interacting elements such as enhancers, insulators, or promoters. To map these elements and interactions, we developed HIPPIE2 which analyzes raw reads from high-throughput chromosome conformation (Hi-C) experiments to identify fine-scale physically-interacting regions (PIRs). Unlike standard genome binning approaches (e.g., 10K-1Mbp bins), HIPPIE2 dynamically calls physical locations of PIRs with better precision and higher resolution based on the pattern of restriction events and relative locations of interacting sites inferred from the sequencing readout.

We applied HIPPIE2 to in situ Hi-C datasets across 6 human cell lines (GM12878, IMR90, K562, HMEC, HUVEC, NHEK) with matched ENCODE and Roadmap functional genomic data. HIPPIE2 detected 1,042,738 distinct PIRs across cell lines, with high resolution (average PIR length of 1,006bps) and high reproducibility (92.3% in GM12878 replicates). 32.8% of PIRs were shared among cell lines. PIRs are enriched for epigenetic marks (H3K27ac, H3K4me1) and open chromatin, suggesting active regulatory roles. HIPPIE2 identified 2.8M significant intrachromosomal PIR–PIR interactions, 27.2% of which were enriched for TF binding sites. 50,608 interactions were enhancer–promoter interactions and were enriched for 33 TFs (31 in enhancers/29 in promoters), several of which are known to mediate DNA looping/long-distance regulation. 29 TFs were enriched in >1 cell line and 4 were cell line-specific. These findings demonstrate that the dynamic approach used in HIPPIE2 (https://bitbucket.com/wanglab-upenn/HIPPIE2) characterizes PIR–PIR interactions with high resolution and reproducibility.
Computational Analysis of Therapeutic Neuroadaptation to Chronic Antidepressant in a Model of the Monoaminergic Neurotransmitter, Stress Hormone, and Male Sex Hormone Systems
Authors: Camacho Mariam Bonyadi , Vijitbenjaronk Warut D. , Anastasio Thomas J
Published: May 2019

Second-line depression treatment involves augmentation with one (rarely two) additional drugs, of chronic administration of a selective serotonin reuptake inhibitor (SSRI), which is the first-line depression treatment. Unfortunately, many depressed patients still fail to respond even after months to years of searching to find an effective combination. To aid in the identification of potentially affective antidepressant combinations, we created a computational model of the monoaminergic neurotransmitter (serotonin, norepinephrine, and dopamine), stress-hormone (cortisol), and male sex-hormone (testosterone) systems. The model was trained via machine learning to represent a broad set of empirical observations. Neuroadaptation to chronic drug administration was simulated through incremental adjustments in model parameters that corresponded to key regulatory components of the neurotransmitter and neurohormone systems. Analysis revealed that neuroadaptation in the model depended on all of the regulatory components in complicated ways, and did not reveal any one or a few specific components that could be targeted in the design of combination antidepressant treatment. We used large sets of neuroadapted states of the model to screen 74 different drug and hormone combinations and identified several combinations that could potentially be therapeutic for a higher proportion of male patients than SSRIs by themselves.
The cell cycle in Staphylococcus aureus is regulated by an amidase that controls peptidoglycan synthesis
Authors: Do Truc , Schaefer Kaitlin , Santiago Ace George , Coe Kathryn A. , Fernandes Pedro B. , Kahne Daniel , Pinho Mariana G. , Walker Suzanne
Published: May 2019

Bacteria are protected by a polymer of peptidoglycan that serves as an exoskeleton. In Staphylococcus aureus, the enzymes that assemble peptidoglycan move during the cell cycle from the periphery, where they are active during growth, to the division site where they build the partition between daughter cells. But how peptidoglycan synthesis is regulated throughout the cell cycle is not understood. Here we identify a membrane protein complex that spatially regulates S. aureus peptidoglycan synthesis. This complex consists of an amidase that removes peptide chains from uncrosslinked peptidoglycan and a partner protein that controls its activity. Typical amidases act after cell division to hydrolyze peptidoglycan between daughter cells so they can separate. However, we show that this amidase controls cell growth. In its absence, excess peptidoglycan synthesis occurs at the cell periphery, causing cells to grow so large that cell division is defective. We show that cell growth and division defects due to loss of this amidase can be mitigated by attenuating the polymerase activity of the major S. aureus peptidoglycan synthase. Our findings lead to a model wherein the amidase complex regulates the density of peptidoglycan assembly sites to control peptidoglycan synthase activity at a given cellular location. Removal of peptide chains from peptidoglycan at the cell periphery promotes synthase movement to midcell during cell division. This mechanism ensures that cell expansion is properly coordinated with cell division.
CellO: Comprehensive and hierarchical cell type classification of human cells with the Cell Ontology
Authors: Bernstein Matthew N. , Ma Zhongjie , Gleicher Michael , Dewey Colin N.
Published: May 2019

Cell type annotation is a fundamental task in the analysis of single-cell RNA-sequencing data. In this work, we present CellO, a machine learning-based tool for annotating human RNA-seq data with the Cell Ontology. CellO enables accurate and standardized cell type classification by considering the rich hierarchical structure of known cell types, a source of prior knowledge that is not utilized by existing methods. Furthemore, CellO comes pre-trained on a novel, comprehensive dataset of human, healthy, untreated primary samples in the Sequence Read Archive, which to the best of our knowledge, is the most diverse curated collection of primary cell data to date. CellO’s comprehensive training set enables it to run out-of-the-box on diverse cell types and achieves superior or competitive performance when compared to existing state-of-the-art methods. Lastly, CellO’s linear models are easily interpreted, thereby enabling exploration of cell type-specific expression signatures across the ontology. To this end, we also present the CellO Viewer: a web application for exploring CellO’s models across the ontology.

Highlight

We present CellO, a tool for hierarchically classifying cell type from single-cell RNA-seq data against the graph-structured Cell Ontology

CellO is pre-trained on a comprehensive dataset comprising nearly all bulk RNA-seq primary cell samples in the Sequence Read Archive

CellO achieves superior or comparable performance with existing methods while featuring a more comprehensive pre-packaged training set

CellO is built with easily interpretable models which we expose through a novel web application, the CellO Viewer, for exploring cell type-specific signatures across the Cell Ontology

Graphical Abstract
Cross-talk between SIM2s and NFkB regulates cyclooxygenase 2 expression in breast cancer
Authors: Wyatt Garhett , Young Chloe , Crump Lyndsey , Wessells Veronica , Gustafson Tanya , Fan Yang-Yi , Chapkin Robert , Porter Weston , Lyons Traci R
Published: May 2019

Background

Breast cancer is a leading cause of cancer-related death for women in the United States. Thus, there a need to investigate novel prognostic markers and therapeutic strategies. Inflammation raises challenges to both treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFkB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, the gene that encodes for cyclooxygenase 2 (COX-2), which is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in inflammation. Here we investigate the effect of Singleminded 2s, a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFkB and COX-2.

Methods

We utilized in vitro reporter assays, immunoblot analyses, qPCR and immunohistochemical analysis to dissect the relationship between NFκB, SIM2s, and COX-2. Furthermore, we utilized COX-2 targeting strategies to determine tumor suppressive activities.

Results

Our results reveal that SIM2s attenuates the activation of a NFκB via luciferase reporter assays. Furthermore, immunostaining of lysates from breast cancer cells over expressing SIM2s showed reduction in various NFκB signaling proteins, whereas knockdown of SIM2 revealed increases in the same NFκB signaling proteins. Additionally, by increasing NFκB translocation to the nucleus in DCIS.COM cells, we show that NFκB signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NFκB translocation in DCIS.COM cells increases SIM2s expression. We also found that NFκB/p65 represses SIM2 in via dose-dependent manner and when NFκB is suppressed the effect on the SIM2 is negated. Additionally, our CHIP analysis confirms that NFκB/p65 binds directly to SIM2 promoter site and that the NFκB sites in the SIM2 promoter are required for NFkB-mediated suppression of SIM2s. Finally, over expression of SIM2s decreases PTGS2 in vitro and COX-2 staining in vivo while decreasing PTGS2 and/or Cox-2 activity results in re-expression of SIM2. Our findings identify a novel role for SIM2s in NFκB signaling and COX-2 expression.

Conclusions

These findings provide evidence for a mechanism where SIM2s may represses COX-2 expression to provide an overall better prognosis for breast cancer patients.
The Biogeography of Coelurosaurian Theropods and its Impact on their Evolutionary History
Authors: Ding Anyang , Pittman Michael , Upchurch Paul , O’Connor Jingmai , Field Daniel J. , Xu Xing
Published: May 2019

The Coelurosauria are a group of mostly feathered theropods that gave rise to birds, the only dinosaurs that survived the Cretaceous-Paleogene extinction event and are still found today. Between their first appearance in the Middle Jurassic up to the end Cretaceous, coelurosaurs were party to dramatic geographic changes on the Earth’s surface, including the breakup of the supercontinent Pangaea, and the formation of the Atlantic Ocean. These plate tectonic events are thought to have caused vicariance or dispersal of coelurosaurian faunas, influencing their evolution. Unfortunately, few coelurosaurian biogeographic hypotheses are supported by quantitative evidence. Here, we report the first, broadly-sampled quantitative analysis of coelurosaurian biogeography using the likelihood-based package BioGeoBEARS. Mesozoic geographic configurations and changes are reconstructed and employed as constraints in this analysis, including their associated uncertainties. We use a comprehensive time-calibrated coelurosaurian evolutionary tree produced from the Theropod Working Group phylogenetic data matrix. Six biogeographic models in the BioGeoBEARS package with different assumptions about the evolution of spatial distribution are tested against the geographic constraints. Our results statistically favour the DIVALIKE+J and DEC+J models, which allow vicariance and founder events, supporting continental vicariance as an important factor in coelurosaurian evolution. Ancestral range estimation indicates frequent dispersal events via the Apulian Route (connecting Europe and Africa during the Early Cretaceous) and the Bering Land Bridge (connecting North America and Asia during the Late Cretaceous). These quantitative results are consistent with commonly inferred Mesozoic dinosaurian dispersals and continental-fragmentation-induced vicariance events. In addition, we recognise the importance of Europe as a dispersal centre and gateway in the Early Cretaceous, as well as other vicariance events like those triggered by the disappearance of land-bridges.