bluuebunny/crossref_metadata_2025 huggingface dataset:
STEM-22. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES MOLECULAR THERAPY RESPONSE IN GLIOBLASTOMA STEM CELLS
Authors: Yang Kailin , Wang Xiuxing , Wu Qiulian , Kim Leo , Morton Andrew , Gimple Ryan , Prager Briana , Shi Yu , Zhou Wenchao , Bhargava Shruti , Zhu Zhe , Jiang Li , Tao Weiwei , Qiu Zhixin , Zhao Linjie , Zhang Guoxing , Li Xiqing , Agnihotri Sameer , Mischel Paul , Mack Stephen , Bao Shideng , Rich Jeremy
Published: November 2019

Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD) or the critical downstream enzyme, dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
STEM-24. THERAPEUTIC APPROACH OF STEM CELL CARRYING RETROVIRAL REPLICATING VECTORS IN HUMAN GLIOMA MODEL
Authors: Inagaki Akihito , Takahashi Masamichi , Kamijima Shuichi , Hiraoka Kei , Tam Quincy , Faure-Kumar Emmanuelle , Treger Janet , Bogan Brooke , Hacke Katrin , Collins Sara , Jolly Douglas , Kasahara Noriyuki
Published: November 2019

Toca 511, an improved retroviral replicating vectors (RRVs) expressing a codon-optimized cytosine deaminase, has shown highly promising evidence of therapeutic benefit in preclinical and clinical studies for gene therapy of glioma. In the present study, we engineered human mesenchymal stem cells (MSC) as tumor-homing cellular carriers that produce and release RRV, and evaluated the effect of this mode of virus delivery on the time course of intratumoral RRV dissemination. Human MSC isolates were engineered to produce RRV (MSC-RRV). Cytotoxicity assays confirmed efficient prodrug activator function in U-87 glioma cells transduced with vectors produced from MSC-RRV. To evaluate intratumoral migration activity and tumor-homing migration activity in vivo, individual MSC isolates were injected either directly into human glioma xenografts, or into the contralateral brain hemisphere. MSC-RRV isolates showing the highest levels of intratumoral migration activity were selected, and the efficiency of intratumoral dissemination and tumoricidal activity achieved by these isolates was compared against injection of RRV virus preparations in subcutaneous glioma models. Compared to virus injection, MSC-RRV achieved 1.6x-higher levels of tumor transduction (p< 0.05), and 2x-reduced tumor growth (p=0.018) at earlier time points. In short-term survival studies using lower doses of MSC-RRV cells vs. RRV virus injected 14 days post-establishment of intracranial U-87 gliomas, a small but statistically significant prolongation of median survival was seen with intracranial tumors treated with MSC-RRV as compared to RRV (26 vs. 20 days, p< 0.05) after only a single cycle of 5-FC prodrug. Thus, MSC can be employed as mobile tumor-homing RRV-producer cells, which release RRV as they migrate to tumor foci in vivo and actively penetrate into individual tumor masses, resulting in more rapid tumor transduction and earlier therapeutic efficacy, which may be advantageous particularly for multi-focal and metastatic disease. This study was funded by the California Institute for Regenerative Medicine (TR2-01791).
New insights into the neurofibroma tumor cells of origin
Authors: Li Stephen , Chen Zhiguo , Le Lu Q
Published: November 2019

Neurofibromatosis type I (NF1) is a debilitating inherited tumor syndrome affecting around 1 in 3000 people. Patients present with a variety of tumors caused by biallelic loss of the tumor suppressor neurofibromin (NF1), a negative regulator of Ras signaling. While the mechanism of tumor formation is similar in the majority of NF1 cases, the clinical spectrum of tumors can vary depending on spatiotemporal loss of heterozygosity of NF1 in cells derived from the neural crest during development. The hallmark lesions that give NF1 its namesake are neurofibromas, which are benign Schwann cell tumors composed of nervous and fibrous tissue. Neurofibromas can be found in the skin (cutaneous neurofibroma) or deeper in body near nerve plexuses (plexiform neurofibroma). While neurofibromas have been known to be Schwann cell tumors for many years, the exact timing and initiating cell has remained elusive. This has led to difficulties in developing animal models and successful therapies for NF1. A culmination of recent genetic studies has finally begun to shed light on the detailed cellular origins of neurofibromatosis. In this review, we will examine the hunt for neurofibroma tumor cells of origin through a historical lens, detailing the genetic systems used to delineate the source of plexiform and cutaneous neurofibromas. Through these novel findings, we can better understand the cellular, temporal, and developmental context during tumor initiation. By leveraging this data, we hope to uncover new therapeutic targets and mechanisms to treat NF1 patients.
The Association Between Smoke-Free School Policies and Adolescents’ Perceived Antismoking Norms: Moderation by School Connectedness
Authors: Schreuders Michael , van den Putte Bas , Mlinarić Martin , Mélard Nora , Perelman Julian , Richter Matthias , Rimpela Arja , Kuipers Mirte A G , Lorant Vincent , Kunst Anton E
Published: November 2019

Introduction

Many European schools implement smoke-free school policies (SFSPs). SFSPs may decrease adolescent smoking by causing adolescents to perceive stronger antismoking norms, yet there exists no quantitative evidence that indicates for which norms and for whom such effects may occur. This study therefore assessed to what extent adolescents’ perceived antismoking norms among best friends, teachers, and society at large were associated with SFSPs, and whether these associations were moderated by adolescents’ level of school connectedness.

Aims and Methods

Survey data were collected in 2016/2017 on 10,653 adolescents aged 14–16 years old and 315 staff members in 55 schools from seven European cities. Associations of adolescent-perceived SFSPs and staff-reported SFSPs with best friend, teacher, and societal antismoking norms were estimated in multilevel logistic regression models, adjusted for demographics and school-level smoking prevalence. We tested for interaction between school connectedness and SFSPs.

Results

Adolescent-perceived SFSPs were positively associated with antismoking norms by teachers (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 1.15–1.85), were negatively associated with antismoking norms by best friends (OR: 0.81, 95% CI: 0.67–0.99), but were not significantly associated with antismoking norms by society at large (OR: 0.87, 95% CI: 0.74–1.02). All interaction tests between adolescent-perceived SFSPs and school connectedness were nonsignificant. Staff-reported SFSPs were not associated with any norm and showed no significant interaction with school connectedness.

Conclusions

We found that SFSPs are associated with adolescents’ perception of more antismoking norms by teachers, but less antismoking norms by best friends, irrespective of adolescents’ level of school connectedness.

Implications

Smoke-free school policies, just as many other tobacco control policies, are assumed to foster adolescents’ perception of antismoking norms. Still, current evidence does not demonstrate which antismoking norms may be influenced by SFSPs and whether this influence is equal for adolescents with different levels of school connectedness. This study suggests that SFSPs foster adolescents’ perception of antismoking norms by teachers, but may concurrently lead to the perception of less antismoking norms by best friends, irrespective of adolescents’ school connectedness. SFSPs may therefore need to be complemented with interventions that target antismoking norms in adolescent peer groups.
Atherosclerotic Cardiovascular Disease Risk Profile of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate
Authors: Huhn Gregory D , Shamblaw David J , Baril Jean-Guy , Hsue Priscilla Y , Mills Brittany L , Nguyen-Cleary Thai , McCallister Scott , Das Moupali
Published: November 2019

Background

In human immunodeficiency virus (HIV) treatment, tenofovir alafenamide (TAF) is associated with greater increases in all fasting cholesterol subgroups compared with tenofovir disoproxil fumarate (TDF). Because lipid abnormalities may contribute to cardiovascular morbidity and mortality, cardiovascular risk assessment is integral to routine HIV care. This post hoc study evaluates the impact of lipid changes on predicted atherosclerotic cardiovascular disease (ASCVD) risk and statin eligibility in treatment-naive adults living with HIV treated with TAF or TDF.

Methods

Participants (N = 1744) were randomized (1:1) to initiate TAF or TDF, each coformulated with elvitegravir/cobicistat/emtricitabine (studies GS-US-292-0104 and GS-US-292-0111). Eligibility for statin therapy and estimated 10-year ASCVD risk among adults aged 40–79 years treated with TAF or TDF for 96 weeks (W96) were analyzed based on American College of Cardiology/American Heart Association Pooled Cohort Equations. Categorical shifts in 10-year ASCVD risk from <7.5% to ≥7.5% by W96 on TAF versus TDF were calculated.

Results

Participants initiating TAF versus TDF in the overall study population showed small but significant increases in median fasting lipid parameters at W96, including total cholesterol (191 vs 177 mg/dL; P < .001), low-density lipoprotein ([LDL] 119 vs 112 mg/dL; P < .001), and high-density lipoprotein ([HDL] 51 vs 48 mg/dL; P < .001), respectively. At baseline, 18% and 23% on TAF versus TDF had a 10-year ASCVD risk score ≥7.5%, with mean risk scores low overall for TAF versus TDF at baseline (4.9% vs 5.4%; P = .35) and W96 (6.1% vs 6.2%; P = .04). Increases in ASCVD risk from baseline to W96 were driven by both increasing age and changes in total cholesterol (TC) and HDL cholesterol. At W96, TC/HDL ratios (median) were 3.7 for both groups (P = .69). There was no difference between shifts in categorical risk for TAF versus TDF (9% vs 5%; P = .19). Eligibility for high-intensity statin therapy were similar for TAF versus TDF groups (19% vs 21%; P = .47).

Conclusions

Lipid changes with TAF as part of coformulated regimens do not substantively affect CVD risk profiles compared with TDF.
Attention to EU Affairs in the Spanish Parliament: The Role of Credit-Claiming and Issue Saliency Strategies
Authors: Palau Anna M
Published: November 2019

Recent research demonstrates that the salience of EU affairs in domestic parliaments is mainly driven by government parties. This has been interpreted as illustrating the so-called opposition deficit thesis and mainly explained considering governments’ informational advantages and reporting duties. Drawing on a dataset on oral questions introduced in plenary meetings in the Spanish parliament, this article sheds new light on government and opposition MPs’ incentives to raise attention to the EU. Results show that in Spain, where there is no party conflict on European integration, government MPs pay attention to EU affairs following credit-claiming strategies. These strategies are likely in the context of EU events and when the perceived benefits of integration are high, and unlikely under critical junctures, when the EU cannot be framed as a governmental success. Opposition MPs pay less attention to EU affairs but they still use the EU to give visibility to issues that are of interest to their voters.
On the partial breaking of $\mathcal{N}=2$ rigid supersymmetry with a complex hypermultiplet
Authors: El Kinani M N , Vall M
Published: November 2019

We study partial supersymmetry breaking in effective $\mathcal{N}=2$ U$ \left( 1\right) ^{n}$ gauge theory coupled to complex hypermultiplets by using the method of L. Andrianopoli et al., Phys. Lett. B 744, 116 (2015), which we refer to as the ADFT method. We derive the generalization of the symplectic invariant ADFT formula $\zeta _{a}=\frac{1}{2}\varepsilon _{abc}(\mathcal{P}^{bM}\mathcal{C}_{MN}\mathcal{P}^{cN}) $, capturing information on partial breaking. Our extension of this anomaly is expressed as $d_{a}=\frac{1}{2}\varepsilon _{abc}\mathbb{P}^{bM}\mathcal{C}_{MN}\mathbb{P}^{cN}+\mathcal{J}_{a}$. The generalized moment maps $\mathbb{P}^{aM}$ contain $\mathcal{P}^{aM}$ and also depend on electric/magnetic coupling charges $G^{M}=( \eta ^{i},g_{i}) $; the $\mathcal{J}_{a}$ is an extra contribution induced by Killing isometries in the complex hypermatter sector. Using SP$\left(2n,\mathbb{R}\right)$ symplectic symmetry, we also give the $\mathcal{N}=2$ partial breaking condition and derive the model of I. Antoniadis et al., Nucl. Phys. B 863, 471 (2012) by a particular realization of the $d_{a}$ anomaly.
Radiological Studies in Very Low Birth Weight and Extremely Low Birth Weight Neonates: ‘ALARA’ Revisited
Authors: Jeetoo Surjit Damon , Smith Johan , Pitcher Richard Denys
Published: November 2019

Background

Very low birth weight (VLBW) and extremely low birth weight (ELBW) neonates are particularly susceptible to the adverse effects of ionizing radiation. There are limited data on radiographic practice among this population in resource-limited environments.

Aim

To estimate cumulative effective dose (ED) from diagnostic imaging in VLBW (1000–1500 g) and ELBW (<1000 g) neonates in a resource-limited setting.

Method

A retrospective analysis of all diagnostic imaging examinations performed on ELBW and VLBW neonates born in a large South African public-sector tertiary-level hospital from January through June 2015. Data were stratified by birth weight and imaging examination. The ED was estimated according to the method of Puch-Kapst. Non-parametric t-tests compared the number of radiographs and ED in VLBW and ELBW neonates, at 5% significance.

Results

Three hundred and ninety-three neonates with median birth weight 1130 (IQR: 930–1340) g were included; 265 (67%) were VLBW and 128 (33%) ELBW; 48 (12%) died at a median of 7 (IQR: 2–17) days. A median of 2 (IQR: 1–5) radiographs were performed per neonate, with median ED 28.8 (IQR: 14.4–90.8) μSv. The median radiographic exposures for VLBW and ELBW neonates were 1 (IQR: 1–4) and 4 (IQR: 2–9), respectively, (p < 0.0001) with median ED 14.4 (IQR: 14.4–70.4) μSv and 71.2 (IQR: 28.8–169.3) μSv, respectively, (p < 0.0001). Radiographic exposure for VLBW neonates was lower than previously documented for this population.

Conclusion

Neonatal radiographic practice in resource-limited settings has the potential to contribute to the discourse on international best practice.
Research on a forecasting model of tourism traffic volume in theme parks in China
Authors: Mei Zhen-yu , Qiu Hai , Feng Chi , Cheng Yang
Published: November 2019

In this study, a model based on multiple regression analysis is developed to forecast the tourism traffic volume of theme parks. First, the macro, meso and micro factors affecting traffic passenger volume are analysed. Second, SPSS software is used for multivariate regression analysis on data for 10 theme parks from 2014. A tourism traffic volume forecasting model is then proposed. Finally, related data for 2015 is used to validate the model, with results showing a prediction error of 14.1%. All results show that the model has a high predictive ability.
First Report of the Association of Myriogenospora atramentosa with the Plant Genus Hemarthria
Authors: Chen Ko-Hsuan , Blount Ann , Justesen Brittany , Walter Joseph H. , Wallau Marcelo , Liao Hui-Ling
Published: November 2019

Myriogenospora atramentosa is an epibiont fungus that produces black, linear stromata on the leaves of warm-season grasses including Paspalum and Andropogon. Because M. atramentosa is in the family Clavicipitaceae containing several ergot alkaloid-producing fungi, its mycotoxin production and the potential risk to cattle health are of concern. Limpograss (Hemarthria altissima) is a warm-season perennial grass that plays a key role in the cattle industry of the southeastern United States. Limpograss plants with tangletop signs and symptoms were collected in October 2018 from Osceola County, Florida, U.S.A. M. atramentosa was confirmed. M. atramentosa is reported to be associated with the plant genus Hemarthria for the first time, through morphological and molecular investigations. Because of the increasing human usage, animal consumption, and global distribution of H. altissima, understanding its codistribution with M. atramentosa and the potential mycotoxin content is critical to protect plants and animals.
Optimizing Fungicide Inputs for Management of Lettuce Drop Caused by Sclerotinia minor and S. sclerotiorum
Authors: Matheron Michael E. , Porchas Martin
Published: November 2019

Lettuce drop, caused by the soilborne fungi Sclerotinia minor and S. sclerotiorum, continues to be an important disease on this crop in Arizona. Trials were conducted over a 5-year period to compare different fungicides as well as the number, timing, and method of application. Compared with nontreated plots, disease reduction ranging from 49.6 to 61.0% was achieved on lettuce beds containing S. minor and treated with fluopyram + trifloxystrobin, fluazinam, fluxapyroxad + pyraclostrobin, and boscalid. Treatment of beds containing S. sclerotiorum with Coniothyrium minitans, iprodione, and boscalid reduced lettuce drop from 50.6 to 71.5%. No difference in disease control was noted between one and two applications of boscalid in plots containing either pathogen. In the presence of S. minor, beginning the first of two applications of boscalid after seeding did not differ from starting after thinning; however, in plots containing S. sclerotiorum, starting application after seeding was superior to beginning after thinning. Physical incorporation of soil treated with boscalid to a depth of 5.0 cm did not differ from soil treatment without incorporation in plots containing S. minor or S. sclerotiorum. On the other hand, in beds containing S. sclerotiorum, incorporation of soil treated with iprodione improved disease control compared with no incorporation.
Survey Reveals a Broad Range of Fungal Pathogens and an Oomycete on Peonies in the United States
Authors: Garfinkel Andrea R. , Chastagner Gary A.
Published: November 2019

Peonies, Paeonia lactiflora and hybrids, are popular ornamental plants grown in landscapes and as cut flowers. As with many ornamental plants, the information on the etiology of peony diseases is incomplete with varying amounts of detailed descriptive material; sometimes validation of Koch’s postulates is also lacking. In a survey to identify the range of diseases of peony in the United States, samples were obtained from 12 states. Fungal and oomycete plant pathogens recovered from symptomatic, diseased tissue were identified by morphology and BLAST identification of the internal transcribed spacer, glyceraldehyde 3-phosphate dehydrogenase, the 28s large subunit, and/or cytochrome c oxidase subunit 1 gene nucleotide sequences for representative isolates. Ten fungal or oomycete genera were identified, and Koch’s postulates were confirmed for selected plant pathogens found during this survey. New disease reports are generated for several states, including five genera never previously reported on peonies in the United States: a Botryosphaeria sp., multiple Colletotrichum spp., Mycocentrospora acerina, a Phoma sp., and Pilidium concavum. The information gained from this survey will provide plant disease diagnosticians and growers a more comprehensive resource for understanding the regional prevalence of peony diseases and subsequently making better disease management decisions.
Contrasting performance between physically active and sedentary older people playing exergames
Authors: Zangirolami-Raimundo Juliana , Raimundo Rodrigo Daminello , da Silva Talita Dias , de Andrade Paulo Evaristo , Benetti Fernanda Antico , da Silva Paiva Laércio , do Valle Joseane Elza Tonussi Mendes Rossette , de Abreu Luiz Carlos
Published: November 2019

The increase in life expectancy associated with the increase in chronological age and less active people helps in the appearance of chronic and degenerative diseases. The encouragement of physical exercises contributes to older people abandoning sedentarism and preventing such diseases. Exergame is a promising alternative, for making exercise a pleasurable activity.

In this study, we compared the performance of physically active older people with sedentary older people in exergames.

Participants were 83 older adults over 65 years of age, of both sexes, divided into 2 physically active older people (AG) and sedentary older people (CG) groups. The participants performed a task through an exergame called “MoviLetrando” that uses the score, number of hits, number of omissions, and an average time of hits as an evaluation. A characterization questionnaire was applied, with information about sex, age, marital status, economic class, self-rated health, time of use of electronic games, a questionnaire on the practice of physical activity, and the Brunel Mood Scale.

There was a higher exergame score in AG than in CG (P = .003), in the number of correct answers (P = .012). The number of omissions was lower in AG than in CG (P = .023). The mean time of correct answers was lower in AG than in CG (P = .013). The regression analysis revealed a significant finding F (3, 82) = 11.06, P < .001 and showed a prediction ability of 26.9% (r
2 = .269). Three variables remained significantly associated with the score: physical activity was marginally significant (β = .19, P = .06), age (β = −.403, P < .001), depression (β = −.212, P = .028).

Physically active older people perform better when compared with the sedentary older people. Age, depression, and physical activity influence the performance in exergame.
Black holes in the quantum universe
Authors: Giddings Steven B.
Published: November 2019

A succinct summary is given of the problem of reconciling observation of black hole-like objects with quantum mechanics. If quantum black holes behave like subsystems, and also decay, their information must be transferred to their environments. Interactions that accomplish this with ‘minimal’ departure from a standard description are parametrized. Possible sensitivity of gravitational wave or very long baseline interferometric observations to these interactions is briefly outlined.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Searching for long-lived particles at the Large Hadron Collider and beyond
Authors: De Roeck Albert
Published: November 2019

We discuss the hunt for long-lived particles at the Large Hadron Collider. A motivation is given for such searches, and the experimental challenges are presented. It has become clear in the last few years that the present experiments are not optimally equipped to cover the full phase space of possibilities for such scenarios, so recently small additional experiments have been proposed for specific searches.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Searching for supersymmetry and its avatars
Authors: Ellis John
Published: November 2019

Why continue looking for supersymmetry?
Over and above the aesthetic and theoretical motivations from string theory, there are several longstanding pheno- menological motivations for TeV-scale super- symmetry, such as the electroweak scale, and the lightest supersymmetric particle as cold dark matter. Run 1 of the Large Hadron Collider (LHC) has actually provided three extra motivations, namely the stabilization of the electroweak vacuum, and successful predictions for the Higgs mass and couplings.
How to look for it?
There are several examples of emergent supersymmetry, the most recent being on the surfaces of topological insulators, and some sort of effective supersymmetry could be useful for boosting the power of laser arrays. At the LHC, attention is moving towards signatures that had previously been neglected, such as long-lived charged particles—which might be an opportunity for the MoEDAL experiment.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Searches for exotica and dark matter with neutrino telescopes
Authors: Margiotta A.
Published: November 2019

Neutrino telescopes are designed to search for neutrino sources in the Universe, exploiting the Cherenkov light emitted along the path of the charged particles produced in interactions occurring close to the detector volume. Their huge size and the shield offered by large water or ice overburden make them excellent tools to search for exotic and rare particles in the cosmic radiation. In particular, they are sensitive to particles not predicted by the Standard Model that could be messenger of new physics. An overview of the experimental scenario and the relevant results obtained looking for magnetic monopoles, dark matter candidates and other exotic relic particles with neutrino telescopes is given, together with the description of possible new perspectives.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Monopole–antimonopole pair production by magnetic fields
Authors: Rajantie Arttu
Published: November 2019

Quantum electrodynamics predicts that in a strong electric field, electron–positron pairs are produced by the Schwinger process, which can be interpreted as quantum tunnelling through the Coulomb potential barrier. If magnetic monopoles exist, monopole–antimonopole pairs would be similarly produced in strong magnetic fields by the electromagnetic dual of this process. The production rate can be computed using semiclassical techniques without relying on perturbation theory, and therefore it can be done reliably in spite of the monopoles' strong coupling to the electromagnetic field. This article explains this phenomenon and discusses the bounds on monopole masses arising from the strongest magnetic fields in the universe, which are in neutron stars known as magnetars and in heavy ion collision experiments such as lead–lead collisions carried out in November 2018 in the large Hadron collider at CERN. It will also discuss open theoretical questions affecting the calculation.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Nakamurella flava sp. nov., a novel endophytic actinobacterium isolated from Mentha haplocalyx Briq.
Authors: Yan Xiao-Rui , Chen Ming-Sheng , Yang Chao , An Ming-Biao , Li Hong-Ying , Shi Hui-Chang , Tuo Li
Published: November 2019

A Gram-stain-positive, aerobic, coccus-shaped, non-spore-forming actinobacterium, designated strain N5BH11T, was isolated from a surface-sterilized sample of Mentha haplocalyx Briq. collected from Guizhou, PR China and tested by a polyphasic approach to determine its taxonomic position. Strain N5BH11T grew optimally at 30 °C, pH 6.0–7.0. Substrate mycelia and aerial mycelia were not formed, and no diffusible pigments were observed on the media tested. Phylogenetic analysis based on 16S rRNA gene sequence suggested that strain N5BH11T belonged to the genus

Nakamurella

and had the highest 16S rRNA gene sequence similarity to

Nakamurella flavida

DS-52T (98.1 %). The DNA G+C content of strain N5BH11T was 71.6 mol%. The average nucleotide identity values between strain N5BH11T and the type strains of

Nakamurella panacisegetis

,

Nakamurella multipartita

and

Nakamurella lactea

were 74.0, 76.5 and 73.6 %, respectively. The estimated DDH values between strain N5BH11T and the type strains of

N. panacisegetis

,

N. multipartita

and

N. lactea

were 20.3%, 21.4 and 20.2 %, respectively. The cell-wall peptidoglycan contained meso-diaminopimelic acid, and MK-8(H4) was the predominant menaquinone. The predominant polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine and unidentified phospholipids. The major fatty acids were iso-C15 : 0, anteiso-C15 : 0, C16 : 0 and C16 : 1ω7c. On the basis of the results of phylogenetic analysis and phenotypic and chemotaxonomic characteristics, strain N5BH11T represents a novel species of the genus

Nakamurella

, for which the name Nakamurella flava sp. nov. is proposed. The type strain is N5BH11T (=KCTC 49196T=CGMCC 4.7524T).
An epigenetic clock for human skeletal muscle
Authors: Voisin S , Harvey NR , Haupt LM , Griffiths LR , Ashton KJ , Coffey VG , Doering TM , Thompson JM , Benedict C , Cedernaes J , Lindholm ME , Craig JM , Rowlands DS , Sharples AP , Horvath S , Eynon N
Published: November 2019

Background

Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples, and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue.

Methods

To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation arrays (HM27, HM450 or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study (EWAS) of age-associated DNA methylation patterns in skeletal muscle.

Results

The newly developed clock uses 200 CpGs to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 CpGs of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs13.1 years for the pan-tissue clock, p < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vsρ = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions (DMRs) with age in skeletal muscle at a False Discovery Rate < 0.005. However, Gene Set Enrichment Analysis did not reveal any enrichment for Gene Ontologies.

Conclusions

We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an R package calledMEATavailable on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.
How repair-or-dispose decisions under stress can initiate disease progression
Authors: Nold Andreas , Batulin Danylo , Birkner Katharina , Bittner Stefan , Tchumatchenko Tatjana
Published: November 2019

Glia, the helper cells of the brain, are essential in maintaining neural resilience across time and varying challenges: By reacting to changes in neuronal health glia carefully balance repair or disposal of injured neurons to prevent further tissue damage. Malfunction of these interactions is implicated in many neurodegenerative diseases. Reductionist models with a minimal number of parameters provide the opportunity to gain insight into biological functions and inform experimental designs. We introduce such a model that mimics long-term implications of repair-or-dispose decisions. Depending on the functionality of the decision-making process, the model assumes four distinct tissue states: healthy, challenged, primed tissue at risk of acute damage propagation, and chronic neurodegeneration. These states of the model correspond to the progression stages observed in the most common neurodegenerative conditions. The underlying mechanisms are in agreement with experimental observations of glia-neuron crosstalk and reproduce a homeostatic balance between repairing and damage-inducing reactions. The model suggests that the onset of neurodegeneration results from a tug-of-war between two conflicting goals: short-term resilience to stressors vs long-term prevention of tissue damage.
Evidence for prereg posters as a platform for preregistration
Authors: Brouwers Kimberly , Cooke Anne , Chambers Christopher D. , Henson Richard , Tibon Roni
Published: November 2019

Prereg posters are conference posters that present planned scientific projects. We provide preliminary evidence for their value in receiving constructive feedback, promoting open science, and supporting early career researchers.
Exploring Survival Models Associated with MCI to AD Conversion: A Machine Learning Approach
Authors: Orozco-Sanchez Jorge , Trevino Victor , Martinez-Ledesma Emmanuel , Farber Joshua , Tamez-Peña Jose
Published: November 2019

Several studies have documented that structural MRI findings are associated with the presence of early-stage Alzheimer Disease (AD). However, the association of each MRI feature with the rate of conversion from mild cognitive impairment (MCI) to AD in a multivariate setting has not been studied fully. The objective of this work is the comprehensive exploration of four different machine learning (ML) strategies to build MRI-based multivariate Cox regression models. These models evaluated the association of MRI features with the time of MCI to clinical AD conversion. We used 442 MCI subjects from the Alzheimer’s disease Neuroimaging Initiative (ADNI) study. Each subject was described by 346 MRI features and time to AD conversion. Cox regression models then estimated the rate of conversion. Models were built using four ML methodologies in a cross-validation (CV) setting. All the ML methods returned successful Cox models with different CV performances. The best model exhibited a concordance index of 0.84 (95% CI: 0.82-0.86). The final analysis described the hazard ratios (HR) of the top ten MRI features associated with MCI to AD conversion. Our results suggest ML exploration is a viable strategy for building and analyzing survival models that predict subjects at risk of AD conversion.
Trading Mental Effort for Confidence in the Metacognitive Control of Value-Based Decision-Making
Authors: Lee Douglas , Daunizeau Jean
Published: November 2019

Why do we sometimes opt for actions or items that we do not value the most? Under current neurocomputational theories, such preference reversals are typically interpreted in terms of errors that arise from the unreliable signaling of value to brain decision systems. But, an alternative explanation is that people may change their mind because they are reassessing the value of alternative options while pondering the decision. So, why do we carefully ponder some decisions, but not others? In this work, we derive a computational model of the metacognitive control of decisions or MCD. In brief, we assume that fast and automatic processes first provide initial (and largely uncertain) representations of options’ values, yielding prior estimates of decision difficulty. These uncertain value representations are then refined by deploying cognitive (e.g., attentional, mnesic) resources, the allocation of which is controlled by an effort-confidence tradeoff. Importantly, the anticipated benefit of allocating resources varies in a decision-by-decision manner according to the prior estimate of decision difficulty. The ensuing MCD model predicts response time, subjective feeling of effort, choice confidence, changes of mind, and choice-induced preference change and certainty gain. We test these predictions in a systematic manner, using a dedicated behavioral paradigm. Our results provide a quantitative link between mental effort, choice confidence, and preference reversals, which could inform interpretations of related neuroimaging findings.
Modulation of the promoter activation rate dictates the transcriptional response to graded BMP signaling levels in theDrosophilaembryo
Authors: Hoppe Caroline , Bowles Jonathan R. , Minchington Thomas G. , Sutcliffe Catherine , Upadhyai Priyanka , Rattray Magnus , Ashe Hilary L.
Published: November 2019

Morphogen gradients specify cell fates during development, with a classic example being the BMP gradient’s conserved role in embryonic dorsal-ventral axis patterning. Here we elucidate how the BMP gradient is interpreted in theDrosophilaembryo, by combining live imaging with computational modelling to infer transcriptional burst parameters at single cell resolution. By comparing burst kinetics in cells receiving different levels of BMP signaling, we show that BMP signaling controls burst frequency by regulating the promoter activation rate. We provide evidence that the promoter activation rate is influenced by both enhancer and promoter sequences, whereas Pol II loading rate is primarily modulated by the enhancer. Consistent with BMP-dependent regulation of burst frequency, the numbers of BMP target gene transcripts per cell are graded across their expression domains. We suggest that graded mRNA output is a general feature of morphogen gradient interpretation and discuss how this can impact on cell fate decisions.
Intrinsic DNA topology as a prioritization metric in genomic fine-mapping studies
Authors: Ainsworth Hannah C. , Howard Timothy D. , Langefeld Carl D.
Published: November 2019

In genomic fine-mapping studies, some approaches leverage annotation data to prioritize likely functional polymorphisms. However, existing annotation sources often present challenges as many: lack data for novel variants, offer no context for noncoding regions, and/or are confounded with linkage disequilibrium. We propose a novel annotation source – sequence-dependent DNA topology – as a prioritization metric for fine-mapping. DNA topology and function are well-intertwined, and as an intrinsic DNA property, it is readily applicable to any genomic region. Here, we constructed and applied, Minor Groove Width (MGW), as a prioritization metric. Using an established MGW-prediction method, we generated an MGW census for 199,038,197 SNPs across the human genome. Summarizing a SNP’s change in MGW (ΔMGW) as a Euclidean distance, ΔMGW exhibited a strongly right-skewed distribution, highlighting the infrequency of SNPs that generate dissimilar shape profiles. We hypothesized that phenotypically-associated SNPs can be prioritized by ΔMGW. We applied Bayesian and frequentist MGW-prioritization approaches to three non-coding regions associated with System Lupus Erythematosus in multiple ancestries. In two regions, including ΔMGW resolved the association to a single, trans-ancestral, SNP, corroborated by external functional data. Together, this study presents the first usage of sequence-dependent DNA topology as a prioritization metric in genomic association studies.

Graphical Abstract

We hypothesize that SNPs imposing dissimilar minor groove width profiles (ΔMGW) are more likely to alter function. ΔMGW was interrogated genome-wide and then used as a weighting metric for fine-mapping associations.
Is the tryptophan codon of gene vif the Achilles’ heel of HIV-1?
Authors: Leal Élcio , Villanova Fabiola , Barreiros Marta
Published: November 2019

To evaluate the impact of hypermutation to the HIV-1 dissemination at the population level we studied 7072 sequences HIV-1 gene vif retrieved from public databank. From this dataset 857 sequences were selected because they had associated values of CD4+ T lymphocytes counts and viral loads and they were used to assess the correlation between clinical parameters and hypermutation. We found that the frequency of stop codons at sites 5, 11 and 79 ranged from 2.8×10-4 to 4.2×10-4. On the other hand, at codons 21, 38, 70, 89 and 174 the frequency of stop codons ranged from 1.4×10-3to 2.5×10-3. We also found a correlation between clinical parameters and hypermutation where patients harboring proviruses with one or more stop codons at the tryptophan sites of the gene vif had higher CD4+ T lymphocytes counts and lower viral loads compared to the population. Our findings indicate that A3 activity potentially restrains HIV-1 replication because individuals with hypermutated proviruses tend to have lower numbers of RNA copies. However, owing to the low frequency of hypermutated sequences observed in the databank (44 out 7072), it is unlikely that A3 has a significant impact to curb HIV-1 dissemination at the population level.
Three dimensional particle averaging for structural imaging of macromolecular complexes by localization microscopy
Authors: Heydarian Hamidreza , Przybylski Adrian , Schueder Florian , Jungmann Ralf , van Werkhoven Ben , Keller-Findeisen Jan , Ries Jonas , Stallinga Sjoerd , Bates Mark , Rieger Bernd
Published: November 2019

We present an approach for 3D particle fusion in localization microscopy which dramatically increases signal-to-noise ratio and resolution in single particle analysis. Our method does not require a structural template, and properly handles anisotropic localization uncertainties. We demonstrate 3D particle reconstructions of the Nup107 subcomplex of the nuclear pore complex (NPC), cross-validated using multiple localization microscopy techniques, as well as two-color 3D reconstructions of the NPC, and reconstructions of DNA-origami tetrahedrons.
Plugging the hunger gap: Organic farming supports more abundant nutritional resources for bees at critical periods
Authors: Austin Alexander James , Lawson-Handley Lori , Gilbert James
Published: November 2019

Understanding the decline in bee populations and their plant mutualists is of paramount concern for ecosystem health, as well as our future food security. Intensive farming practices are one of the major drivers behind such declines. Organic farming is one of the principal alternatives to conventional practices yet the evidence for its effects are mixed, with some studies showing limited benefits. We conducted bee and floral surveys on 10 paired organic and conventional farms across Yorkshire, UK, to investigate how farming practice influenced the abundance, richness and community composition of bees and flowering plants. Firstly, we found that species richness for flowering plants and bees was similar across organic and conventional farms. Floral composition differed between organic and conventional farms with the greatest differences seen in May and June, whereas bee community composition was similar among farming practices. Secondly, both bee and floral abundance were higher in organic farms. Peaks in floral abundance, and corresponding bee abundance, occurred in particular months, most notably in July, with abundance during the rest of the season being similar across both farming practices. Synthesis and applications: Our results suggest that higher floral availability on organic farms corresponds with increased bee abundance. Of particular importance was the higher floral abundance during spring, in the pollinator 'hungry gap', where floral resources are traditionally scarce. However, conventional farms performed comparably to organic farms across the rest of the season, as well as showing similar levels of species richness, diversity and species composition for both flowering plants and bees. We suggest that targeted management on conventional farms, aimed at boosting floral abundance in the spring, when floral abundance is low, could allow conventional farms to make up the shortfall. Additionally, focusing on increasing the diversity of flowering plants, in terms of both phenology and nutritional composition, for both adult bees and their larvae, could improve bee community diversity across both farming systems.
Dopamine role in learning and action inference
Authors: Bogacz Rafal
Published: November 2019

This paper describes a framework for modelling dopamine function in the mammalian brain. In this framework, dopaminergic neurons projecting to different parts of the striatum encode errors in predictions made by the corresponding systems within the basal ganglia. These prediction errors are equal to differences between rewards and expectations in the goal-directed system, and to differences between the chosen and habitual actions in the habit system. The prediction errors enable learning about rewards resulting from actions and habit formation. During action planning, the expectation of reward in the goal-directed system arises from formulating a plan to obtain that reward. Thus dopaminergic neurons in this system provide feedback on whether the current motor plan is sufficient to obtain the available reward, and they facilitate action planning until a suitable plan is found. Presented models account for dopaminergic responses during movements, effects of dopamine depletion on behaviour, and make several experimental predictions.
Genomic determinants of speciation
Authors: Cong Qian , Zhang Jing , Grishin Nick V.
Published: November 2019

Studies of life rely on classifying organisms into species. However, since Darwin, there is no agreement about how to separate species from varieties. Contrary to a frequent belief, quantitative standards for species delineation are lacking and overdue, and debates about species delimitation create obstacles for conservation biology, agriculture, legislation, and education. To tackle this key biological question, we have chosen butterflies as model organisms. We sequenced and analyzed transcriptomes of 188 specimens representing pairs of close but clearly distinct species, populations, and taxa that are debated among experts. We find that species are robustly separated from populations by the combination of two measures computed on Z-linked genes: fixation index that detects hiatus between species, and the extent of gene flow that quantifies reproductive isolation. These criteria suggest that all 9 butterfly pairs that caused experts’ disagreement are distinct species, not populations. When applied to Homo, our criteria agree that all modern humans are the same species distinct from Neanderthals, suggesting relevance of this study beyond butterflies. Furthermore, we found that proteins involved in interactions with DNA (including proteins encoded by trans-regulatory elements), circadian clock, pheromone sensing, development, and immune response recurrently correlate with speciation. A significant fraction of these proteins is encoded by the Z-chromosome, which appears to be resistant to introgression. Taken together, we find common speciation mechanisms in butterflies, reveal the central role of Z-chromosome in speciation, and suggest quantitative criteria for species delimitation using genomic data, which is vital for the exploration of biodiversity.