bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IICR and the non-stationary structured coalescent: towards demographic inference with arbitrary changes in population structure
Authors: Rodríguez Willy , Mazet Olivier , Grusea Simona , Arredondo Armando , Corujo Josué M. , Boitard Simon , Chikhi Lounès 
Published: October 2018

AbstractIn the last years, a wide range of methods allowing to reconstruct past population size changes from genome-wide data have been developed. At the same time, there has been an increasing recognition that population structure can generate genetic data similar to those produced under models of population size change. Recently, Mazet et al. (Heredity 116:362–371, 2016) showed that, for any model of population structure, it is always possible to find a panmictic model with a particular function of population size changes, having exactly the same distribution ofT2(the coalescence time for a sample of size two) as that of the structured model. They called this function IICR (Inverse Instantaneous Coalescence Rate) and showed that it does not necessarily correspond to population size changes under non-panmictic models. Besides, most of the methods used to analyse data under models of population structure tend to arbitrarily fix that structure and to minimise or neglect population size changes. Here, we extend the seminal work of Herbots (PhD thesis, University of London, 1994) on the structured coalescent and propose a new framework, the Non-Stationary Structured Coalescent (NSSC) that incorporates demographic events (changes in gene flow and/or deme sizes) to models of nearly any complexity. We show how to compute the IICR under a wide family of stationary and non-stationary models. As an example we address the question of human and Neanderthal evolution and discuss how the NSSC framework allows to interpret genomic data under this new perspective.
Lin−CCR2+ hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
Authors: Flores Catherine T. , Wildes Tyler J. , Drake Jeffrey A. , Moore Ginger L. , Dean Bayli DiVita , Abraham Rebecca S. , Mitchell Duane A. 
Published: October 2018

AbstractImmune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C–C chemokine receptor type 2 (CCR2+) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2+HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8+ T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2+HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.
DRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery
Authors: Ye Chaoyang , Ho Daniel J. , Neri Marilisa , Yang Chian , Kulkarni Tripti , Randhawa Ranjit , Henault Martin , Mostacci Nadezda , Farmer Pierre , Renner Steffen , Ihry Robert , Mansur Leandra , Keller Caroline Gubser , McAllister Gregory , Hild Marc , Jenkins Jeremy , Kaykas Ajamete 
Published: October 2018

AbstractHere we report Digital RNA with pertUrbation of Genes (DRUG-seq), a high-throughput platform for drug discovery. Pharmaceutical discovery relies on high-throughput screening, yet current platforms have limited readouts. RNA-seq is a powerful tool to investigate drug effects using transcriptome changes as a proxy, yet standard library construction is costly. DRUG-seq captures transcriptional changes detected in standard RNA-seq at 1/100th the cost. In proof-of-concept experiments profiling 433 compounds across 8 doses, transcription profiles generated from DRUG-seq successfully grouped compounds into functional clusters by mechanism of actions (MoAs) based on their intended targets. Perturbation differences reflected in transcriptome changes were detected for compounds engaging the same target, demonstrating the value of using DRUG-seq for understanding on and off-target activities. We demonstrate DRUG-seq captures common mechanisms, as well as differences between compound treatment and CRISPR on the same target. DRUG-seq provides a powerful tool for comprehensive transcriptome readout in a high-throughput screening environment.
Nanoscale metal-organic frameworks for mitochondria-targeted radiotherapy-radiodynamic therapy
Authors: Ni Kaiyuan , Lan Guangxu , Veroneau Samuel S. , Duan Xiaopin , Song Yang , Lin Wenbin 
Published: October 2018

AbstractSelective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT). Though cationic Ru-based photosensitizers accumulate in mitochondria, they require excitation with less penetrating short-wavelength photons, limiting their application in PDT. We recently discovered X-ray based cancer therapy by nanoscale metal–organic frameworks (nMOFs) via enhancing radiotherapy (RT) and enabling radiodynamic therapy (RDT). Herein we report Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT. Constructed from Ru-based photosensitizers, the cationic framework exhibits strong mitochondria-targeting property. Upon X-ray irradiation, Hf-DBB-Ru efficiently generates hydroxyl radicals from the Hf6 SBUs and singlet oxygen from the DBB-Ru photosensitizers to lead to RT-RDT effects. Mitochondria-targeted RT-RDT depolarizes the mitochondrial membrane to initiate apoptosis of cancer cells, leading to significant regression of colorectal tumors in mouse models. Our work establishes an effective strategy to selectively target mitochondria with cationic nMOFs for enhanced cancer therapy via RT-RDT with low doses of deeply penetrating X-rays.
The effect of the stress hormone cortisol on the metatranscriptome of the oral microbiome
Authors: Duran-Pinedo Ana E. , Solbiati Jose , Frias-Lopez Jorge 
Published: October 2018

AbstractImbalances of the microbiome, also referred to as microbial dysbiosis, could lead to a series of different diseases. One factor that has been shown to lead to dysbiosis of the microbiome is exposure to psychological stressors. Throughout evolution microorganisms of the human microbiome have developed systems for sensing host-associated signals such as hormones associated with those stressors, enabling them to recognize essential changes in their environment, thus changing their expression gene profile to fit the needs of the new environment. The most widely accepted theory explaining the ability of hormones to affect the outcome of an infection involves the suppression of the immune system. Commensal microbiota is involved in stressor-induced immunomodulation, but other biological effects are not yet known. Here we present the impact that cortisol had on the community-wide transcriptome of the oral community. We used a metatranscriptomic approach to obtain first insights into the metabolic changes induced by this stress hormone as well as which members of the oral microbiome respond to the presence of cortisol in the environment. Our findings show that the stress hormone cortisol directly induces shifts in the gene expression profiles of the oral microbiome that reproduce results found in the profiles of expression of periodontal disease and its progression.
Understanding the Stability of Salt-Inclusion Phases for Nuclear Waste-forms through Volume-based Thermodynamics
Authors: Moore Emily E. , Kocevski Vancho , Juillerat Christian A. , Morrison Gregory , Zhao Mingyang , Brinkman Kyle S. , Loye Hans-Conrad zur , Besmann Theodore M. 
Published: October 2018

AbstractFormation enthalpies and Gibbs energies of actinide and rare-earth containing SIMs with silicate and germanate frameworks are reported. Volume-based thermodynamics (VBT) techniques complemented by density functional theory (DFT) were adapted and applied to these complex structures. VBT and DFT results were in closest agreement for the smaller framework silicate structure, whereas DFT in general predicts less negative enthalpies across all SIMs, regardless of framework type. Both methods predict the rare-earth silicates to be the most stable of the comparable structures calculated, with VBT results being in good agreement with the limited experimental values available from drop solution calorimetry.
Antagonistic and cooperative AGO2-PUM interactions in regulating mRNAs
Authors: Sternburg Erin L. , Estep Jason A. , Nguyen Daniel K. , Li Yahui , Karginov Fedor V. 
Published: October 2018

AbstractApproximately 1500 RNA-binding proteins (RBPs) profoundly impact mammalian cellular function by controlling distinct sets of transcripts, often using sequence-specific binding to 3′ untranslated regions (UTRs) to regulate mRNA stability and translation. Aside from their individual effects, higher-order combinatorial interactions between RBPs on specific mRNAs have been proposed to underpin the regulatory network. To assess the extent of such co-regulatory control, we took a global experimental approach followed by targeted validation to examine interactions between two well-characterized and highly conserved RBPs, Argonaute2 (AGO2) and Pumilio (PUM1 and PUM2). Transcriptome-wide changes in AGO2-mRNA binding upon PUM knockdown were quantified by CLIP-seq, and the presence of PUM binding on the same 3′UTR corresponded with cooperative and antagonistic effects on AGO2 occupancy. In addition, PUM binding sites that overlap with AGO2 showed differential, weakened binding profiles upon abrogation of AGO2 association, indicative of cooperative interactions. In luciferase reporter validation of candidate 3′UTR sites where AGO2 and PUM colocalized, three sites were identified to host antagonistic interactions, where PUM counteracts miRNA-guided repression. Interestingly, the binding sites for the two proteins are too far for potential antagonism due to steric hindrance, suggesting an alternate mechanism. Our data experimentally confirms the combinatorial regulatory model and indicates that the mostly repressive PUM proteins can change their behavior in a context-dependent manner. Overall, the approach underscores the importance of further elucidation of complex interactions between RBPs and their transcriptome-wide extent.
A comprehensive anatomical map of the peripheral octopaminergic/tyraminergic system of Drosophila melanogaster
Authors: Pauls Dennis , Blechschmidt Christine , Frantzmann Felix , el Jundi Basil , Selcho Mareike 
Published: October 2018

AbstractThe modulation of an animal’s behavior through external sensory stimuli, previous experience and its internal state is crucial to survive in a constantly changing environment. In most insects, octopamine (OA) and its precursor tyramine (TA) modulate a variety of physiological processes and behaviors by shifting the organism from a relaxed or dormant condition to a responsive, excited and alerted state. Even though OA/TA neurons of the central brain are described on single cell level inDrosophila melanogaster, the periphery was largely omitted from anatomical studies. Given that OA/TA is involved in behaviors like feeding, flying and locomotion, which highly depend on a variety of peripheral organs, it is necessary to study the peripheral connections of these neurons to get a complete picture of the OA/TA circuitry. We here describe the anatomy of this aminergic system in relation to peripheral tissues of the entire fly. OA/TA neurons arborize onto skeletal muscles all over the body and innervate reproductive organs, the heart, the corpora allata, and sensory organs in the antennae, legs, wings and halteres underlining their relevance in modulating complex behaviors.
Correlated bursts in temporal networks slow down spreading
Authors: Hiraoka Takayuki , Jo Hang-Hyun 
Published: October 2018

AbstractSpreading dynamics has been considered to take place in temporal networks, where temporal interaction patterns between nodes show non-Poissonian bursty nature. The effects of inhomogeneous interevent times (IETs) on the spreading have been extensively studied in recent years, yet little is known about the effects of correlations between IETs on the spreading. In order to investigate those effects, we study two-step deterministic susceptible-infected (SI) and probabilistic SI dynamics when the interaction patterns are modeled by inhomogeneous and correlated IETs, i.e., correlated bursts. By analyzing the transmission time statistics in a single-link setup and by simulating the spreading in Bethe lattices and random graphs, we conclude that the positive correlation between IETs slows down the spreading. We also argue that the shortest transmission time from one infected node to its susceptible neighbors can successfully explain our numerical results.
Oral formulation of DPP-4 inhibitor plus Quercetin improves metabolic homeostasis in type 1 diabetic rats
Authors: Miranda Pedro Henrique de A. , Lacerda Kissyla Christine Duarte , Araújo Carolina Morais , Barichello José Mario , Lima Wanderson Geraldo , Costa Daniela Caldeira 
Published: October 2018

AbstractThis study aimed to investigate the potential of an oral formulation (QV formulation) containing Quercetin and a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), Vildagliptin, in improving metabolic homeostasis in type 1 diabetes model. Female albino Fischer rats were divided into four groups: untreated control animals (C), untreated diabetic animals (D), diabetic animals treated with QV formulation (DQV), and diabetic animals treated with insulin (DI). Diabetes was induced by injection of alloxan (135 mg kg body mass)−1 and confirmed by glycemic test. After the 30-day treatment period, biochemical parameters were analyzed in the pancreas, liver, and serum. Histopathological changes in pancreatic tissue were examined by Hematoxyline & Eosin staining and the insulin content in the islet measured by immunohistochemistry with anti-insulin antibody. The glycogen content in the hepatocytes was quantified by Periodic Schiff Acid staining. The QV formulation reduced the glycemia, preserved the pancreatic architecture, increased insulin levels, furthermore ameliorated lipid profile and to promote higher survival rate of animals. Together, our data suggest that the QV formulation treatment was able to normalize metabolic homeostasis in type 1 diabetic rats.
Fidelity of CMIP5 multi-model mean in assessing Indian monsoon simulations
Authors: Mishra Saroj K. , Sahany Sandeep , Salunke Popat , Kang In-Sik , Jain Shipra 
Published: October 2018

AbstractConsidering the wide use of the multi-model mean (MMM) on the seasonal time scale, this work examines its fidelity in simulating some important characteristics of the Indian summer monsoon using Coupled Model Intercomparison Project Phase 5 (CMIP5) simulations. It is noted that the MMM captures the observed spatial pattern and annual cycle of surface air temperature to a great extent, but there are large biases in magnitude, particularly over north India. For precipitation, only the broad-scale features are captured and extreme large biases, of magnitude equal or higher than the seasonal mean precipitation, exist in the MMM. The simulation of trends in seasonal mean temperatures and precipitation is even less satisfactory than the climatological means. Several precipitation features, for example, low-to-moderate intensity precipitation events, orography-related rain bands, extreme events, are noted to improve with increasing resolution of the models, whereas, no such improvement is noted for temperatures. It is also noted that the improvement in CMIP5 MMM is marginal if compared with the best performing model from the group of models considered for analysis. There are several models that show similar skill as MMM, and therefore could be alternatively used for future projections. Moreover, using such individual models for Indian monsoon projections will also help us to understand the underlying mechanisms and processes by conducting targeted numerical experiments, which would otherwise be highly limited by approaches like MMM. Therefore, targeted efforts to improve some of these better models are required to gain more confidence in future projections of Indian monsoon.
Performance analysis of epoxy nanocomposites due to water droplet‐initiated discharges under AC and DC voltages and localisation of discharges
Authors: Mishra Palash , Desai B.M. Ashwin , Sarathi Ramanujam , Imai Takahiro 
Published: October 2018

Corona inception voltage (CIV) due to water droplet sitting over the surface of epoxy nanocomposite material depends on supply voltage frequency, the conductivity of water droplet and the contact angle of the test specimens. The contact angle of the specimen and CIV due to water droplet has a direct correlation. It is realised that the CIV is high under negative DC and the least under AC voltages. Surface charge accumulation studies indicate that the accumulated charge and its decay time constant reduces in the damage‐caused zone due to corona activity. The ultra‐high frequency (UHF) signal generated due to water droplet‐initiated corona activity has frequency content in the range of 0.8–1 GHz. The localisation of incipient discharges is demonstrated by using the non‐iterative technique and the cross recurrence plot (CRP) technique is used to estimate the time difference of arrival (TDOA) of UHF signals generated due to water droplet‐initiated discharge. Laser‐induced breakdown spectroscopy (LIBS) depicts the elemental composition and reveals the difference in plasma temperature and threshold fluence between all the test specimens. In short, the performance of ion trapping particle filled epoxy nanocomposite performance is found to be best followed by titania filled epoxy nanocomposite and the base epoxy resin.
Guided by Evolution: Biology-Oriented Synthesis of Bioactive Compound Classes
Authors: Karageorgis George , Waldmann Herbert 
Published: October 2018

Biology-oriented-synthesis (BIOS), is a chemocentric approach to identifying structurally novel molecules as tools for chemical biology and medicinal chemistry research. The vast chemical space cannot be exhaustively covered by synthetic chemistry. Thus, methods which reveal biologically relevant portions of chemical space are of high value. Guided by structural conservation in the evolution of both proteins and natural products, BIOS classifies bioactive compound classes in a hierarchical manner based on molecular architecture and bioactivity. Biologically relevant scaffolds inspire and guide the synthesis of BIOS libraries, which calls for the development of suitable synthetic methodologies. These compound collections have enriched biological relevance, leading to the discovery of bioactive small molecules. These potent and selective modulators allow the study of complex biological pathways and may serve as starting points for drug discovery programs. Thus, BIOS can also be regarded as a hypothesis-generating tool, guiding the design and preparation of novel, bioactive molecular scaffolds. This review elaborates the principles of BIOS and highlights selected examples of their application, which have in turn created future opportunities for the expansion of BIOS and its combination with fragment-based compound discovery for the identification of biologically relevant small molecules with unprecedented molecular scaffolds.1	Introduction2	Structural Classification of Natural Products3	Implications and Opportunities for Biology-Oriented Synthesis4	Applications of Biology-Oriented Synthesis4.1	Chemical Structure and Bioactivity Guided Approaches4.2	Natural-Product-Derived Fragment-Based Approaches5	Conclusions and Outlook
Screening for risk of low energy availability in athletic and recreationally active females in Ireland
Authors: Logue Danielle M. , Madigan Sharon M. , Heinen Mirjam , McDonnell Sarah‐Jane , Delahunt Eamonn , Corish Clare A. 
Published: October 2018

ABSTRACTIntroduction: Low energy availability (LEA) results in physiological adaptations, which can contribute to unfavourable health outcomes. Little information exists on risk of LEA in active individuals competing in different sports or levels of competition. The aims of this study were to (1) identify risk of LEA in females competing at different levels of competition and (2) investigate associations between risk of LEA, illness and dietary habits. Methods: The validated questionnaire, ‘Low Energy Availability in Females Questionnaire’ was distributed online (November 2016–February 2017) to assess risk of LEA. Twenty‐nine additional questions collected information on demographics, illness history and dietary habits. Participants were considered at risk of LEA if they attained a score of ≥ 8 and were grouped into: (i) international; (ii) provincial/inter‐county; (iii) competitive; and (iv) recreationally active. Chi‐square and logistic regression analyses were used to explore differences between those at risk or not at risk of LEA. Results: Risk of LEA was identified in 40% (n = 331) of 833 participants and was 1.7 and 1.8 times more likely in international and provincial/inter‐county athletes compared to those who were recreationally active (International: odds ratios (OR) 1.68, 95% confidence intervals (95%CI) 1.12–2.54; Provincial/inter‐county: OR 1.83, 95%CI 1.20–2.77). In participants at risk of LEA, missing >22 days of training during the previous year due to illness occurred 3 times more frequently (OR 3.01, 95%CI 1.81–5.02). Conclusion: Risk of LEA was widespread in this heterogeneous sample. Awareness of LEA and the development of appropriate energy management strategies to ensure athlete health across levels of competition are required.
Alterations in core temperature during World Rugby Sevens Series tournaments in temperate and warm environments†
Authors: Taylor Lee , Thornton Heidi R. , Lumley Nick , Stevens Christopher J. 
Published: October 2018

AbstractPurpose: To characterize player core temperature (Tc) across two separate World Rugby Sevens Series (WRSS) tournaments in temperate and warm environments. Methods: Tc was collected in seventeen playing members of one men's team competing at the Singapore (n = 12) and London (n = 11) WRSS tournaments. Exertional heat illness (EHI) symptoms, cooling strategy use, playing minutes and wet blub globe temperature (WBGT) were also collected. Linear mixed models and magnitude‐based inferences assessed differences in Tc between all periods within‐and between tournaments and were also used to assess the effect of WBGT and playing minutes on Tc. Results: Several players experienced Tc in excess of 38°C during warm‐ups and 39°C during games. The highest mean Tc values were observed in the final game on all days and in Singapore Day Two, there were substantial game‐on‐game increases in mean Tc. These Tc responses were associated with playing minutes (effect size; ±90% CL = 0.38; ±0.20), although the effect of WBGT was trivial and unclear. Further, there were no differences in Tc between the two tournaments in the different environments. Despite high individual peak Tc values (Singapore 39.9°C; London 39.6°C); no signs/symptoms of EHI were reported, voluntary post‐game cooling usage was minimal, and pre‐ and mid‐cooling strategies were not implemented. Conclusions: During WRSS matches, peak Tc values approached thresholds associated with EHI (>40°C) and exceeded those demonstrated to reduce repeated sprint performance (>39°C). Practitioners may consider the use of compatible cooling and heat acclimation strategies to minimize Tc increase and maximize player preparedness and recovery.