bluuebunny/crossref_metadata_2025 huggingface dataset:
Preferential attachment when stable
Authors: Janson Svante , Sen Subhabrata , Spencer Joel
Published: November 2019

We study an urn process with two urns, initialized with a ball each. Balls are added sequentially, the urn being chosen independently with probability proportional to the $\alpha$th power $(\alpha >1)$ of the existing number of balls. We study the (rare) event that the urn compositions are balanced after the addition of $2n-2$ new balls. We derive precise asymptotics of the probability of this event by embedding the process in continuous time. Quite surprisingly, fine control of this probability may be leveraged to derive a lower-tail large deviation principle (LDP) for $L = \sum_{i=1}^{n} ({S_i^2}/{i^2})$, where $\{S_n \colon n \geq 0\}$ is a simple symmetric random walk started at zero. We provide an alternative proof of the LDP via coupling to Brownian motion, and subsequent derivation of the LDP for a continuous-time analog of L. Finally, we turn our attention back to the urn process conditioned to be balanced, and provide a functional limit law describing the trajectory of the urn process.
On the ergodicity of a class of level-dependent quasi-birth-and-death processes
Authors: Cordeiro James D. , Kharoufeh Jeffrey P. , Oxley Mark E.
Published: November 2019

We examine necessary and sufficient conditions for recurrence and positive recurrence of a class of irreducible, level-dependent quasi-birth-and-death (LDQBD) processes with a block tridiagonal structure that exhibits asymptotic convergence in the rows as the level tends to infinity. These conditions are obtained by exploiting a multi-dimensional Lyapunov drift approach, along with the theory of generalized Markov group inverses. Additionally, we highlight analogies to well-known average drift results for level-independent quasi-birth-and-death (QBD) processes.
Cluster Expansions for GIBBS Point Processes
Authors: Jansen S.
Published: November 2019

We provide a sufficient condition for the uniqueness in distribution of Gibbs point processes with non-negative pairwise interaction, together with convergent expansions of the log-Laplace functional, factorial moment densities and factorial cumulant densities (correlation functions and truncated correlation functions). The criterion is a continuum version of a convergence condition by Fernández and Procacci (2007), the proof is based on the Kirkwood–Salsburg integral equations and is close in spirit to the approach by Bissacot, Fernández, and Procacci (2010). In addition, we provide formulas for cumulants of double stochastic integrals with respect to Poisson random measures (not compensated) in terms of multigraphs and pairs of partitions, explaining how to go from cluster expansions to some diagrammatic expansions (Peccati and Taqqu, 2011). We also discuss relations with generating functions for trees, branching processes, Boolean percolation and the random connection model. The presentation is self-contained and requires no preliminary knowledge of cluster expansions.
Towards a Comprehensive Framework for Understanding EU Enforcement Regimes
Authors: VAN KREIJ Laurens
Published: November 2019

Next to Member States, European Union (EU) level organisations have come to play a larger role in enforcement in the EU during the last two decades. Analysing the roles of Member States, networks of national authorities and EU agencies in this stage of the policy cycle through multiple academic lenses could lead to a more comprehensive understanding and assessment of their design. This article sets elementary steps towards a framework that brings together prominent theoretical insights from the legal and political disciplines, to discuss their combined leverage for understanding the EU legislator's choice for these enforcement regimes.
Response of snowpack to +2°C global warming in Hokkaido, Japan
Authors: Katsuyama Yuta , Inatsu Masaru , Shirakawa Tatsuo
Published: November 2019

The response of snowpack to a +2°C global warming relative to the present climate was estimated in Hokkaido, Japan, using a physical snowpack model driven by dynamically downscaled (DDS) data, after model evaluation. The evaluation revealed that the snowpack model successfully reproduced the height of snow cover (HS), snow water equivalent (SWE) and snow-covered days (SCDs), but had a moderate bias in the thickness ratios of melt form (MF) and hoar category (HC). The DDS-forced simulation predicted that the seasonal-maximum HS and SWE would decrease by 30–40% in the southwestern and eastern parts of Hokkaido due to a large decrease in snowfall during the accumulation period, and that the HS and SWE in the north would decrease, albeit not significantly due to uncertain atmospheric forcing. The number of SCDs in Hokkaido was predicted to decline by ~30 d. Additionally, ~50% of snowpack thickness during a season would be MF in most areas, whereas HC would be <50% all over Hokkaido.
Personality Traits and Consumption of Wine and Beer
Authors: Gustavsen Geir W. , Rickertsen Kyrre
Published: November 2019

Little attention has been paid to the effects of personality traits on the consumption of wine and beer. We used a survey to investigate the associations between personality traits and the differences in expected consumption frequencies of wine and beer for 3,482 Norwegian respondents. High scores on extraversion and openness to experiences increased the expected frequency of wine consumption, high score on agreeableness reduced the frequency of wine consumption, while scores on conscientiousness and neuroticism had no effects. For beer, there were no significant effects between personality traits and the frequency of consumption. (JEL Classification: D12, Q13).
Technology and protest: the political effects of electronic voting in India
Authors: Desai Zuheir , Lee Alexander
Published: November 2019

Electronic voting technology is often proposed as translating voter intent to vote totals better than alternative systems such as paper ballots. We suggest that electronic voting machines (EVMs) can also alter vote choice, and, in particular, the way in which voters register anti-system sentiment. This paper examines the effects of the introduction of EVMs in India, the world's largest democracy, using a difference-in-differences methodology that takes advantage of the technology's gradual introduction. We find that EVMs are associated with dramatic declines in the incidence of invalid votes, and corresponding increases in vote for minor candidates. There is ambiguous evidence for EVMs decreasing turnout, no evidence for increases in rough proxies of voter error or fraud, and no evidence that machines with an auditable paper trail perform differently from other EVMs. The results highlight the interaction between voter technology and voter protest, and the substitutability of different types of protest voting.
The glycation level of milk protein strongly modulates post-prandial lysine availability in humans
Authors: Nyakayiru Jean , van Lieshout Glenn A. A. , Trommelen Jorn , van Kranenburg Janneau , Verdijk Lex B. , Bragt Marjolijn C. E. , van Loon Luc J. C.
Published: November 2019

Industrial heat treatment of milk results in protein glycation. A high protein glycation level has been suggested to compromise the post-prandial rise in plasma amino acid availability following protein ingestion. In the present study, we assessed the impact of glycation level of milk protein on post-prandial plasma amino acid responses in humans. Fifteen healthy, young men (age 26 (SEM 1) years, BMI 24 (SEM 1) kg/m2) participated in this randomised cross-over study and ingested milk protein powder with protein glycation levels of 3, 20 and 50 % blocked lysine. On each trial day, arterialised blood samples were collected at regular intervals during a 6-h post-prandial period to assess plasma amino acid concentrations using ultra-performance liquid chromatography. Plasma essential amino acid (EAA) concentrations increased following milk protein ingestion, with the 20 and 50 % glycated milk proteins showing lower overall EAA responses compared with the 3 % glycated milk protein (161 (SEM 7) and 142 (SEM 7) v. 178 (SEM 9) mmol/l × 6 h, respectively; P ≤ 0·011). The lower post-prandial plasma amino acid responses were fully attributed to an attenuated post-prandial rise in circulating plasma lysine concentrations. Plasma lysine responses (incremental AUC) following ingestion of the 20 and 50 % glycated milk proteins were 35 (SEM 4) and 92 (SEM 2) % lower compared with the 3 % glycated milk protein (21·3 (SEM 1·4) and 2·8 (SEM 0·7) v. 33·3 (SEM 1·7) mmol/l × 6 h, respectively; P < 0·001). Milk protein glycation lowers post-prandial plasma lysine availability in humans. The lower post-prandial availability of lysine following ingestion of proteins with a high glycation level may compromise the anabolic properties of a protein source.
Assessing the global conservation status of the rock rose Helianthemum caput-felis
Authors: Sulis Elena , Bacchetta Gianluigi , Cogoni Donatella , Gargano Domenico , Fenu Giuseppe
Published: November 2019

The assessment of the conservation status of a species is the first step in developing a conservation strategy. IUCN Red Lists assessments are an important starting point for conservation actions and the most commonly applied method for assessing the extinction risk of a species. In this study, the global conservation status of the rock rose Helianthemum caput-felis Boiss. (Cistaceae), a perennial Mediterranean plant, was evaluated using the Red List criteria. The distribution of the species was determined by monitoring historical localities and all other suitable sites along the western Mediterranean coasts for 6 years. For each confirmed locality, the ecological and population parameters and the main threats were recorded; these data were used in a quantitative analysis of the species' extinction risk. Our findings indicate there have been several recent extinctions, and there is a continuing decline in the species' area of occurrence, habitat quality and number of reproductive plants. The main threats are related to human activities. Extinction models indicate a probability of quasi-extinction risk of c. 30% in five generations or c. 45% in three generations, with the species likely to become extinct in seven currently known localities within the next 10 years. Application of the Red List criteria indicates H. caput-felis should be categorized as Endangered. This study confirms that legal protection and passive conservation measures are insufficient to guarantee the persistence of a plant species. Active conservation and management actions are needed to protect this and other threatened species of the Mediterranean Basin.
High prevalence of Schistosoma haematobium × Schistosoma bovis hybrids in schoolchildren in Côte d'Ivoire
Authors: Angora Etienne K. , Allienne Jean-François , Rey Olivier , Menan Hervé , Touré André O. , Coulibaly Jean T. , Raso Giovanna , Yavo William , N'Goran Eliézer K. , Utzinger Jürg , Balmer Oliver , Boissier Jérôme
Published: November 2019

Schistosomiasis is a neglected tropical disease, though it is highly prevalent in many parts of sub-Saharan Africa. While Schistosoma haematobium-bovis hybrids have been reported in West Africa, no data about Schistosoma hybrids in humans are available from Côte d'Ivoire. This study aimed to identify and quantify S. haematobium-bovis hybrids among schoolchildren in four localities of Côte d'Ivoire. Urine samples were collected and examined by filtration to detect Schistosoma eggs. Eggs were hatched and 503 miracidia were individually collected and stored on Whatman® FTA cards for molecular analysis. Individual miracidia were molecularly characterized by analysis of mitochondrial cox1 and nuclear internal transcribed spacer 2 (ITS 2) DNA regions. A mitochondrial cox1-based diagnostic polymerase chain reaction was performed on 459 miracidia, with 239 (52.1%) exhibiting the typical band for S. haematobium and 220 (47.9%) the S. bovis band. The cox1 and ITS 2 amplicons were Sanger sequenced from 40 randomly selected miracidia to confirm species and hybrids status. Among the 33 cox1 sequences analysed, we identified 15 S. haematobium sequences (45.5%) belonging to seven haplotypes and 18 S. bovis sequences (54.5%) belonging to 12 haplotypes. Of 40 ITS 2 sequences analysed, 31 (77.5%) were assigned to pure S. haematobium, four (10.0%) to pure S. bovis and five (12.5%) to S. haematobium-bovis hybrids. Our findings suggest that S. haematobium-bovis hybrids are common in Côte d'Ivoire. Hence, intense prospection of domestic and wild animals is warranted to determine whether zoonotic transmission occurs.
Genetic differentiation and diversity of sugarbeet germplasm resistant to the sugarbeet root maggot
Authors: Fugate Karen K. , Campbell Larry G. , Covarrubias-Pazaran Giovanny , Rodriguez-Bonilla Lorraine , Zalapa Juan
Published: November 2019

Germplasm lines with resistance to the sugarbeet root maggot (SBRM) have been developed and released to the public, providing a means to generate hybrids with resistance against the most devastating insect pest of sugarbeet in North America. Effective use of this germplasm, however, requires knowledge of relative strengths of SBRM resistance between lines and knowledge of the diversity and genetic relationships between germplasm. Therefore, field studies comparing SBRM resistance of four released SBRM-resistant germplasm lines (F1015, F1016, F1024 and F1043), a SBRM-resistant parent (PI 179180) and an unreleased SBRM-resistant population (F1055) were performed, and genetic analysis of the diversity and relationships between SBRM-resistant germplasm and their available parents was conducted using simple sequence repeat (SSR) markers. Under natural SBRM infestations, resistant germplasm exhibited significantly less SBRM damage than a susceptible control, with similar, high levels of resistance in F1016, F1024, F1043, F1055 and PI 179180 and lower resistance in F1015. SSR analysis revealed genetic similarities between F1016, F1024 and F1055, while F1015 and F1043 were genetically distinct from these lines. Among resistant genotypes, F1015 and F1043 exhibited greatest and least within-line genetic diversity, indicating greater and lesser inbreeding for F1043 and F1015, respectively. Similarities in damage ratings and genetics for F1016, F1024 and F1055 indicate that these lines are likely to be equally effective at introducing SBRM resistance into elite populations and in combining ability. In contrast, F1043, with its unique parentage and genetic dissimilarity from other resistant lines, provides a genetically distinct, but similarly effective, source of SBRM resistance.
NICANDER'SHYMN TO ATTALUS: PERGAMENE PANEGYRIC
Authors: Nelson Thomas J.
Published: November 2019

This paper looks beyond Ptolemaic Alexandria to consider the literary dynamics of another Hellenistic kingdom, Attalid Pergamon. I offer a detailed study of the fragmentary opening of Nicander'sHymn to Attalus(fr. 104 Gow–Schofield) in three sections. First, I consider its generic status and compare its encomiastic strategies with those of Theocritus’Encomium of Ptolemy Philadelphus(Idyll17). Second, I analyse its learned reuse of the literary past and allusive engagement with scholarly debate. And finally, I explore how Nicander polemically strives against the precedent of the Ptolemaic Callimachus. The fragment offers us a rare glimpse into the post-Callimachean, international and agonistic world of Hellenistic poetics.
An encapsulated fruit, vegetable and berry juice powder concentrate increases plasma values of specific carotenoids and vitamins
Authors: Dams Sebastian , Holasek Sandra , Tsiountsioura Melina , Malliga Daniela-Eugenia , Meier-Allard Nathalie , Poncza Brigitte , Lackner Sonja , Jansenberger Yvonne , Lamprecht Manfred
Published: November 2019

Abstract. Vitamins and carotenoids are organic compounds that are important for vital functions of the human organism. Since the human body is not able to synthesize most of these micronutrients, they need to be supplied by the intake of food or supplements. The aim of this study was to analyze whether a whole food based, encapsulated fruit, berry, and vegetable juice powder concentrate provides bioavailable carotenoids and vitamins A (all-trans retinol), E and C. Eighteen healthy subjects received 6 capsules a day for 8 weeks, which provided 2.91 mg β-carotene, 490 μg vitamin A, 18.7 mg vitamin E, 159 mg vitamin C, 6.1 mg lutein and 1 mg lycopene. Plasma concentrations of several carotenoids and vitamins before and after supplementation were measured. After 8 weeks of supplementation, the plasma concentration of the following carotenoids increased significantly: α-carotene increased from 59.6 ± 22.4 nmol/L to 85.7 ± 24.2 nmol/L (p = 0.002), β-cryptoxanthin from 106.7 ± 39.8 nmol/L to 151.9 ± 57.9 nmol/L (p = 0.017), and lycopene from 1.2 ± 0.5 μmol/L to 1.7 ± 0.5 μmol/L (p = 0.005). Significant increases were also observed for plasma concentrations of vitamin C from 70 ± 20 μmol/L to 90 ± 10 μmol/L (p < 0.001), all-trans retinol from 1.99 ± 0.24 μmol/L to 2.30 ± 0.66 μmol/L (p = 0.015), and α-tocopherol from 27 ± 6 μmol/L to 32 ± 6 μmol/L (p = 0.008). For those micronutrients with accepted plasma reference ranges, all observed increases levelled off around the upper limit of the individual reference range. The data demonstrate that the investigated supplement is able to increase plasma concentrations of certain carotenoids and vitamins of healthy subjects within 8 weeks.
The Accommodation of the South Flank's Motion by the Koa‘e Fault System, Kīlauea, Hawai‘i: Insights From the June 2012 Earthquake Sequence
Authors: Ge Shuangyu , Lin Guoqing , Amelung Falk , Okubo Paul G. , Swanson Donald A. , Yunjun Zhang
Published: November 2019

The Koa‘e fault system is a prominent and complex structural element of Kīlauea Volcano, Hawai‘i. On 5 June 2012, a sequence of shallow earthquakes occurred in the central part of the Koa‘e fault system. The Interferometric Synthetic Aperture Radar (InSAR) data from multiple satellites spanning the time of the earthquake occurrence indicate a maximum of ~10‐cm surface displacement above the seismic events in the Koa‘e. The Global Positioning System (GPS) data from multiple stations show that there was a slow slip event in the south flank in late May 2012. Field visits to the fault after the earthquakes revealed ground cracks. In this study, we combine the seismic, InSAR, GPS data, and field observations to investigate the characteristics of the Koa‘e fault system. We relocate the seismic events in the central part of the Koa‘e fault system, compute the focal mechanisms for the events in the June 2012 earthquake sequence, invert for a two‐fault model based on the surface deformation, and discuss their relationships with the 2012 slow slip event. Based on our Coulomb stress‐change calculation, we infer that the 2012 slow slip event may have triggered both the seismic events and the surface deformation and played a major role in the evolution of the Koa‘e fault system and the accommodation of the south flank's motion. Our integrated analyses are helpful to constrain the fault geometry in the Koa‘e system and to shed light on the role of Koa‘e in the structural evolution of Kīlauea.
Frequency‐Dependent P Wave Polarization and Its Subwavelength Near‐Surface Depth Sensitivity
Authors: Park Sunyoung , Tsai Victor C. , Ishii Miaki
Published: November 2019

Near‐surface structure is crucial to assessing seismic hazards and understanding earthquakes and surface processes yet is a major challenge to robustly image. Recently, an approach based on body‐wave polarization was introduced for constraining shallow seismic structure, but the depth sensitivity of the polarization measurement has remained unclear. Using waveform simulations based on a layer over a half space, we find that the depth sensitivity of P wave polarization peaks at the surface and decreases abruptly over a depth range shorter than its wavelength. A strong frequency dependence provides constraints on local 1‐D structure, with frequencies between 0.1 and 10 Hz illuminating structure at depths of 10 m to several kilometers. Applying these results to teleseismic recordings in Japan provides constraints on structure at about 120 to 750 m, including a distinctive weak zone along the Median Tectonic Line in the Kii peninsula and Awaji Island.
Tibetan Plateau's Lake Level and Volume Changes From NASA's ICESat/ICESat‐2 and Landsat Missions
Authors: Zhang Guoqing , Chen Wenfeng , Xie Hongjie
Published: November 2019

Lake level change is an effective indicator of climate change, because it reflects the dynamic balance of water input and loss. Here we provide a first look of Ice, Cloud, and land Elevation Satellite‐2 (ICESat‐2) on the lakes of the Tibetan Plateau. ICESat‐2 doubles the number of lakes observed using predecessor ICESat data. The ICESat/ICESat‐2 altimetry data between 2003 and 2018 are in excellent agreement with in situ measurements from Qinghai Lake (R2 = 0.95, root‐mean‐square error = 0.10 m) and with gauge observations made on 3 December 2018 (< 2 cm). The 62 lakes examined show a mean rate of water level change of 0.28 ± 0.03 m/year in 2003–2018, with 58 lakes increasing (mean rate 0.30 ± 0.03 m/year), and 4 lakes decreasing (mean rate −0.12 ± 0.06 m/year). A total change of lake water storage of ~14 Gt/year is estimated. The results suggest that ICESat‐2 data will be an important tool for future lake level change studies.
Early Dynamics of the Lunar Core
Authors: Ćuk Matija , Hamilton Douglas P. , Stewart Sarah T.
Published: November 2019

The Moon is known to have a small liquid core, and it is thought that in the distant past the core may have produced strong magnetic fields recorded in lunar samples. Here we implement a numerical model of lunar orbital and rotational dynamics that includes the effects of a liquid core. In agreement with previous work, we find that the lunar core is dynamically decoupled from the lunar mantle and that this decoupling happened very early in lunar history. Our model predicts that the lunar core rotates subsynchronously, and the difference between the core and the mantle rotational rates was significant when the Moon had a high forced obliquity during and after the Cassini State transition. We find that the presence of the lunar liquid core further destabilizes synchronous rotation of the mantle for a wide range of semimajor axes centered around the Cassini State transition. Core‐mantle boundary torques make it even more likely that the Moon experienced large‐scale inclination damping during the Cassini State transition. We present estimates for the mutual core‐mantle obliquity as a function of Earth‐Moon distance, and we discuss plausible absolute time lines for this evolution. We conclude that our results are consistent with the hypothesis of a precession‐driven early lunar dynamo and may explain the variability of the inferred orientation of the past lunar dynamo.
MarsWRF Convective Vortex and Dust Devil Predictions for Gale Crater Over 3 Mars Years and Comparison With MSL‐REMS Observations
Authors: Newman C. E. , Kahanpää H. , Richardson M. I. , Martínez G. M. , Vicente‐Retortillo A. , Lemmon M. T.
Published: November 2019

Key Points

MarsWRF output combined with thermodynamic theory is used to predict spatiotemporal trends of dust devil activity (DDA) in Gale Crater

Both modeled DDA and number of observed vortex pressure drops are greatest in local summer, peaking ~13:00–14:00, and smallest in winter

Stronger sensible heat fluxes and winds drive a rise in DDA as MSL climbs, but vortex numbers rise faster, unless a threshold DDA is used
MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53
Authors: Wang Yingchao , Wang Gaoxiong , Tan Xionghong , Ke Kun , Zhao Bixing , Cheng Niangmei , Dang Yuan , Liao Naishun , Wang Fei , Zheng Xiaoyuan , Li Qin , Liu Xiaolong , Liu Jingfeng
Published: November 2019

Poor prognosis of hepatocellular carcinoma (HCC) patients is frequently associated with rapid tumor growth, recurrence and drug resistance. MT1G is a low-molecular weight protein with high affinity for zinc ions. In the present study, we investigated the expression of MT1G, analyzed clinical significance of MT1G, and we observed the effects of MT1G overexpression on proliferation and apoptosis of HCC cell lines in vitro and in vivo. Our results revealed that MT1G was significantly downregulated in tumor tissues, and could inhibit the proliferation as well as enhance the apoptosis of HCC cells. The mechanism study suggested that MT1G increased the stability of p53 by inhibiting the expression of its ubiquitination factor, MDM2. Furthermore, MT1G also could enhance the transcriptional activity of p53 through direct interacting with p53 and providing appropriate zinc ions to p53. The modulation of MT1G on p53 resulted in upregulation of p21 and Bax, which leads cell cycle arrest and apoptosis, respectively. Our in vivo assay further confirmed that MT1G could suppress HCC tumor growth in nude mice. Overall, this is the first report on the interaction between MT1G and p53, and adequately uncover a new HCC suppressor which might have therapeutic values by diminishing the aggressiveness of HCC cells.
Androgen receptor expression and response to chemotherapy in breast cancer patients treated in the neoadjuvant TECHNO and PREPARE trial
Authors: Witzel Isabell , Loibl Sibylle , Wirtz Ralph , Fasching Peter A. , Denkert Carsten , Weber Karsten , Lück Hans-Joachim , Huober Jens , Karn Thomas , Mackelenbergh Marion von , Marmé Frederik , Schem Christian , Stickeler Elmar , Untch Michael , Müller Volkmar
Published: November 2019

Background

The androgen receptor (AR) is discussed as a prognostic and/or predictive marker in breast cancer patients.

Methods

AR mRNA expression was analysed by RT-qPCR in breast cancer patients treated in the neoadjuvant TECHNO (n  =  118, HER2-positive) and PREPARE trial (n  =  321, HER2-positive and -negative). In addition, mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured.

Results

Regarding subtypes, high AR mRNA levels were frequent in HER2-positive (61.3%, 92/150) and luminal tumours (60.0%, 96/160) but almost absent in triple-negative tumours (4.3%, 3/69) (p < 0.0001). Overall, high AR mRNA levels were found to be associated with lower pathological complete remission (pCR) rates (OR 0.77 per unit, 95% CI 0.67–0.88, p  =  0.0002) but also with better prognosis in terms of longer disease-free survival (DFS) (HR 0.57, 95% CI 0.39–0.85, p  =  0.0054) and overall survival (OS) (HR 0.43, 95% CI, 0.26–0.71, p  =  0.0011). In the PREPARE trial, a survival difference for patients with high and low AR1 mRNA levels could only be seen in the standard chemotherapy arm but not in the dose-dense treatment arm (OS: HR 0.41; 95% CI 0.22–0.74 vs. HR 1.05; 95% CI 0.52–2.13; p  =  0.0459).

Conclusions

We provide evidence that AR mRNA predicts response to chemotherapy in breast cancer patients.
Duplication and transcriptional divergence of three Kunitz protease inhibitor genes that modulate insect and pathogen defenses in tea plant (Camellia sinensis)
Authors: Zhu Junyan , He Yaxian , Yan Xiaomei , Liu Lu , Guo Rui , Xia Xiaobo , Cheng Daojie , Mi Xiaozeng , Samarina Lidiia , Liu Shenrui , Xia Enhua , Wei Chaoling
Published: November 2019

Kunitz protease inhibitors (KPIs) are ubiquitous in plants and act as crucial compounds in defense responses against insect attack and pathogen infection. However, the influence of gene duplication on the postdivergence of theCsKPIgenes involved in biotic stresses in tea plant is not well known. Here, we identified threeCsKPIgenes from tea plant (Camellia sinensis) and characterized their expression and evolutionary patterns among plant species. We found thatCsKPI1,CsKPI2, andCsKPI3diverged from their common ancestor 72.94 million years ago (MYA), and the tandem duplication ofCsKPI2andCsKPI3occurred 26.78 MYA. An in vitro protein assay showed that the three CsKPI proteins were functional and inhibited the production ofp-nitroanilide (PNA) from an artificial substrate. The three CsKPI-GFP fusion proteins localized to the cytoplasm. We showed that salicylic acid (SA) and transcripts ofCsKPI2andCsKPI3significantly accumulated after infection withGlomerella cingulata. The application of exogenous SA stimulated the high expression of bothCsKPI2andCsKPI3by activatingcis-elements within their promoters. UnderEctropis obliqueattack,CsKPI1expression and jasmonic acid (JA) levels were more abundant in both insect-damaged leaf tissues and undamaged neighboring leaves. The application of jasmonic acid methyl ester elicited high expression levels ofCsKPI1, suggesting thatCsKPI1accumulation requires JA production in tea plant. The overall findings suggest that the transcriptional divergence of KPI genes after duplication led to the specialized role ofCsKPI1in the physiological response to insect stress; the functional conservation betweenCsKPI2andCsKPI3confers resistance to pathogen infection in tea plant.
Adaptive prospective optical gating enables day-long 3D time-lapse imaging of the beating embryonic zebrafish heart
Authors: Taylor Jonathan M. , Nelson Carl J. , Bruton Finnius A. , Kaveh Aryan , Buckley Charlotte , Tucker Carl S. , Rossi Adriano G. , Mullins John J. , Denvir Martin A.
Published: November 2019

Three-dimensional fluorescence time-lapse imaging of the beating heart is extremely challenging, due to the heart’s constant motion and a need to avoid pharmacological or phototoxic damage. Although real-time triggered imaging can computationally “freeze” the heart for 3D imaging, no previous algorithm has been able to maintain phase-lock across developmental timescales. We report a new algorithm capable of maintaining day-long phase-lock, permitting routine acquisition of synchronised 3D + time video time-lapse datasets of the beating zebrafish heart. This approach has enabled us for the first time to directly observe detailed developmental and cellular processes in the beating heart, revealing the dynamics of the immune response to injury and witnessing intriguing proliferative events that challenge the established literature on cardiac trabeculation. Our approach opens up exciting new opportunities for direct time-lapse imaging studies over a 24-hour time course, to understand the cellular mechanisms underlying cardiac development, repair and regeneration.
Genetic variants of calcium and vitamin D metabolism in kidney stone disease
Authors: Howles Sarah A. , Wiberg Akira , Goldsworthy Michelle , Bayliss Asha L. , Gluck Anna K. , Ng Michael , Grout Emily , Tanikawa Chizu , Kamatani Yoichiro , Terao Chikashi , Takahashi Atsushi , Kubo Michiaki , Matsuda Koichi , Thakker Rajesh V. , Turney Benjamin W. , Furniss Dominic
Published: November 2019

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45–60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.
Quantum chemistry as a benchmark for near-term quantum computers
Authors: McCaskey Alexander J. , Parks Zachary P. , Jakowski Jacek , Moore Shirley V. , Morris Titus D. , Humble Travis S. , Pooser Raphael C.
Published: November 2019

We present a quantum chemistry benchmark for noisy intermediate-scale quantum computers that leverages the variational quantum eigensolver, active-space reduction, a reduced unitary coupled cluster ansatz, and reduced density purification as error mitigation. We demonstrate this benchmark using 4 of the available qubits on the 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen processors via the simulation of alkali metal hydrides (NaH, KH, RbH), with accuracy of the computed ground state energy serving as the primary benchmark metric. We further parameterize this benchmark suite on the trial circuit type, the level of symmetry reduction, and error mitigation strategies. Our results demonstrate the characteristically high noise level present in near-term superconducting hardware, but provide a relevant baseline for future improvement of the underlying hardware, and a means for comparison across near-term hardware types. We also demonstrate how to reduce the noise in post processing with specific error mitigation techniques. Particularly, the adaptation of McWeeny purification of noisy density matrices dramatically improves accuracy of quantum computations, which, along with adjustable active space, significantly extends the range of accessible molecular systems. We demonstrate that for specific benchmark settings and a selected range of problems, the accuracy metric can reach chemical accuracy when computing over the cloud on certain quantum computers.
CPEM: Accurate cancer type classification based on somatic alterations using an ensemble of a random forest and a deep neural network
Authors: Lee Kanggeun , Jeong Hyoung-oh , Lee Semin , Jeong Won-Ki
Published: November 2019

With recent advances in DNA sequencing technologies, fast acquisition of large-scale genomic data has become commonplace. For cancer studies, in particular, there is an increasing need for the classification of cancer type based on somatic alterations detected from sequencing analyses. However, the ever-increasing size and complexity of the data make the classification task extremely challenging. In this study, we evaluate the contributions of various input features, such as mutation profiles, mutation rates, mutation spectra and signatures, and somatic copy number alterations that can be derived from genomic data, and further utilize them for accurate cancer type classification. We introduce a novel ensemble of machine learning classifiers, called CPEM (Cancer Predictor using an Ensemble Model), which is tested on 7,002 samples representing over 31 different cancer types collected from The Cancer Genome Atlas (TCGA) database. We first systematically examined the impact of the input features. Features known to be associated with specific cancers had relatively high importance in our initial prediction model. We further investigated various machine learning classifiers and feature selection methods to derive the ensemble-based cancer type prediction model achieving up to 84% classification accuracy in the nested 10-fold cross-validation. Finally, we narrowed down the target cancers to the six most common types and achieved up to 94% accuracy.
Microbial changes in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients
Authors: Laheij Alexa M. G. A. , Raber-Durlacher Judith E. , Koppelmans Renée G. A. , Huysmans Marie-Charlotte D. N. J. M. , Potting Carin , van Leeuwen Stephanie J. M. , Hazenberg Mette D. , Brennan Michael T. , von Bültzingslöwen Inger , Johansson Jan-Erik , de Soet Johannes J. , Haverman Thijs M. , Buijs Mark J. , Brandt Bernd W. , Rozema Frederik R. , Blijlevens Nicole M. A. , Zaura Egija
Published: November 2019

The aim of this prospective, two center study was to investigate the dynamics of the microbial changes in relation to the development of ulcerative oral mucositis in autologous SCT (autoSCT) recipients. Fifty-one patients were diagnosed with multiple myeloma and treated with high-dose melphalan followed by autoSCT. They were evaluated before, three times weekly during hospitalization, and three months after autoSCT. At each time point an oral rinse was collected and the presence or absence of ulcerative oral mucositis (UOM) was scored (WHO scale). Oral microbiome was determined by using 16S rRNA amplicon sequencing and fungal load by qPCR. Twenty patients (39%) developed UOM. The oral microbiome changed significantly after autoSCT and returned to pre-autoSCT composition after three months. However, changes in microbial diversity and similarity were more pronounced and rapid in patients who developed UOM compared to patients who did not. Already before autoSCT, different taxa discriminated between the 2 groups, suggesting microbially-driven risk factors. Samples with high fungal load (>0.1%) had a significantly different microbial profile from samples without fungi. In conclusion, autoSCT induced significant and reversible changes in the oral microbiome, while patients who did not develop ulcerative oral mucositis had a more resilient microbial ecosystem.
mTORC1 activity is essential for erythropoiesis and B cell lineage commitment
Authors: Malik Natasha , Dunn Karen M. , Cassels Jennifer , Hay Jodie , Estell Christopher , Sansom Owen J. , Michie Alison M.
Published: November 2019

Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates phosphoinositide-3-kinase (PI3K)/AKT signalling. This pathway is involved in a plethora of cellular functions including protein and lipid synthesis, cell migration, cell proliferation and apoptosis. In this study, we proposed to delineate the role of mTORC1 in haemopoietic lineage commitment using knock out (KO) mouse and cell line models. Mx1-cre and Vav-cre expression systems were used to specifically target Raptorfl/fl (mTORC1), either in all tissues upon poly(I:C) inoculation, or specifically in haemopoietic stem cells, respectively. Assessment of the role of mTORC1 during the early stages of development in Vav-cre+Raptorfl/fl mice, revealed that these mice do not survive post birth due to aberrations in erythropoiesis resulting from an arrest in development at the megakaryocyte-erythrocyte progenitor stage. Furthermore, Raptor-deficient mice exhibited a block in B cell lineage commitment. The essential role of Raptor (mTORC1) in erythrocyte and B lineage commitment was confirmed in adult Mx1-cre+Raptorfl/fl mice upon cre-recombinase induction. These studies were supported by results showing that the expression of key lineage commitment regulators, GATA1, GATA2 and PAX5 were dysregulated in the absence of mTORC1-mediated signals. The regulatory role of mTOR during erythropoiesis was confirmed in vitro by demonstrating a reduction of K562 cell differentiation towards RBCs in the presence of established mTOR inhibitors. While mTORC1 plays a fundamental role in promoting RBC development, we showed that mTORC2 has an opposing role, as Rictor-deficient progenitor cells exhibited an elevation in RBC colony formation ex vivo. Collectively, our data demonstrate a critical role played by mTORC1 in regulating the haemopoietic cell lineage commitment.
Machine Learning to Quantitate Neutrophil NETosis
Authors: Elsherif Laila , Sciaky Noah , Metts Carrington A. , Modasshir Md. , Rekleitis Ioannis , Burris Christine A. , Walker Joshua A. , Ramadan Nadeem , Leisner Tina M. , Holly Stephen P. , Cowles Martis W. , Ataga Kenneth I. , Cooper Joshua N. , Parise Leslie V.
Published: November 2019

We introduce machine learning (ML) to perform classification and quantitation of images of nuclei from human blood neutrophils. Here we assessed the use of convolutional neural networks (CNNs) using free, open source software to accurately quantitate neutrophil NETosis, a recently discovered process involved in multiple human diseases. CNNs achieved >94% in performance accuracy in differentiating NETotic from non-NETotic cells and vastly facilitated dose-response analysis and screening of the NETotic response in neutrophils from patients. Using only features learned from nuclear morphology, CNNs can distinguish between NETosis and necrosis and between distinct NETosis signaling pathways, making them a precise tool for NETosis detection. Furthermore, by using CNNs and tools to determine object dispersion, we uncovered differences in NETotic nuclei clustering between major NETosis pathways that is useful in understanding NETosis signaling events. Our study also shows that neutrophils from patients with sickle cell disease were unresponsive to one of two major NETosis pathways. Thus, we demonstrate the design, performance, and implementation of ML tools for rapid quantitative and qualitative cell analysis in basic science.
Maximal information transmission is compatible with ultrasensitive biological pathways
Authors: Micali Gabriele , Endres Robert G.
Published: November 2019

Cells are often considered input-output devices that maximize the transmission of information by converting extracellular stimuli (input) via signaling pathways (communication channel) to cell behavior (output). However, in biological systems outputs might feed back into inputs due to cell motility, and the biological channel can change by mutations during evolution. Here, we show that the conventional channel capacity obtained by optimizing the input distribution for a fixed channel may not reflect the global optimum. In a new approach we analytically identify both input distributions and input-output curves that optimally transmit information, given constraints from noise and the dynamic range of the channel. We find a universal optimal input distribution only depending on the input noise, and we generalize our formalism to multiple outputs (or inputs). Applying our formalism toEscherichia colichemotaxis, we find that its pathway is compatible with optimal information transmission despite the ultrasensitive rotary motors.
PD-1+ melanocortin receptor dependent-Treg cells prevent autoimmune disease
Authors: Muhammad Fauziyya , Wang Dawei , Montieth Alyssa , Lee Stacey , Preble Janine , Foster C. Stephen , Larson Theresa A. , Ding Kai , Dvorak Justin D. , Lee Darren J.
Published: November 2019

Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1+FoxP3+ Tregs in uveitis patients was similar compared to healthy controls, but was significantly reduced with melanocortin stimulation. Further, lower body mass index correlated with responsiveness to stimulation of this pathway. These observations indicate an importance of the PD-1/PD-L1 pathway to provide resistance to relapsing uveitis and shows a reduced capacity of uveitis patients to induce Tregs when stimulated through melanocortin receptors, but that it is possible to bypass this part of the pathway through direct stimulation of A2Ar.
The peptide AC 2 isolated from Bacillus-treated Trapa japonica fruit extract rescues DHT (dihydrotestosterone)-treated human dermal papilla cells and mediates mTORC1 signaling for autophagy and apoptosis suppression
Authors: Nam Gun He , Jo Kyung-Jo , Park Ye-Seul , Kawk Hye Won , Yoo Je-Geun , Jang Jin Dong , Kang Sang Moon , Kim Sang-Yong , Kim Young-Min
Published: November 2019

The Trapa japonica fruit is a natural plant growing in ponds with its roots in the mud. It has long been used as a home remedy for many diseases; however, a major problem with this kind of natural extract is the multicomponents-multitargets for diseases. Such problems make it difficult to identify the mechanism of action. Another problem is quality control and consistency. The aim of this research was to isolate a single bioactive compound (peptide) derived from the Trapa japonica fruit. The research was conducted with various experimental techniques, such as fermentation and liquid chromatography, to isolate a peptide. We isolated the AC 2 peptide from Trapa japonica fruit and found it to be promising on human dermal papilla cells. Dihydrotestosterone (DHT) stresses human dermal papilla cells and is a major cause of hair loss resulting from hormones and environmental factors. The purpose of this research was to develop an understanding of the mechanism by which the AC 2 peptide rescues dihydrotestosterone (DHT)-treated human dermal papilla cells. We explored the effects of the AC 2 peptide on the cell biological functions of human dermal papilla cells (HDPs). HDPs were treated with the AC 2 peptide and DHT. Then, a cytotoxicity assay, flow cytometry, Western blot, immunoprecipitation, and 3D cell culture for immunohistochemistry were conducted to investigate the mTORC1 pathway and suppression of autophagy and apoptosis. In addition, we also synthesized the AC2 peptide as an alternative to the expensive and difficult isolation and purification procedures and confirmed its potential in biomedical applications. We also validated the effects of the synthetic AC2 peptide as well as the isolated and purified AC2 peptide and established their similarity. Although extensive research has been carried out on natural extracts, few single studies have isolated and separated a bioactive peptide (single compound).
Computed terahertz near-field mapping of molecular resonances of lactose stereo-isomer impurities with sub-attomole sensitivity
Authors: Moon Kiwon , Do Youngwoong , Park Hongkyu , Kim Jeonghoi , Kang Hyuna , Lee Gyuseok , Lim Jin-Ha , Kim Jin-Woo , Han Haewook
Published: November 2019

Terahertz near-field microscopy (THz-NFM) could locally probe low-energy molecular vibration dynamics below diffraction limits, showing promise to decipher intermolecular interactions of biomolecules and quantum matters with unique THz vibrational fingerprints. However, its realization has been impeded by low spatial and spectral resolutions and lack of theoretical models to quantitatively analyze near-field imaging. Here, we show that THz scattering-type scanning near-field optical microscopy (THz s-SNOM) with a theoretical model can quantitatively measure and image such low-energy molecular interactions, permitting computed spectroscopic near-field mapping of THz molecular resonance spectra. Using crystalline-lactose stereo-isomer (anomer) mixtures (i.e., α-lactose (≥95%, w/w) and β-lactose (≤4%, w/w)), THz s-SNOM resolved local intermolecular vibrations of both anomers with enhanced spatial and spectral resolutions, yielding strong resonances to decipher conformational fingerprint of the trace β-anomer impurity. Its estimated sensitivity was ~0.147 attomoles in ~8 × 10−4 μm3 interaction volume. Our THz s-SNOM platform offers a new path for ultrasensitive molecular fingerprinting of complex mixtures of biomolecules or organic crystals with markedly enhanced spatio-spectral resolutions. This could open up significant possibilities of THz technology in many fields, including biology, chemistry and condensed matter physics as well as semiconductor industries where accurate quantitative mappings of trace isomer impurities are critical but still challenging.