bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of the Nonlinearities on Gaussian Pulses Propagation in Photonic Crystal Fiber
Authors: Jasim M.S. , Sultan H.A. , Emshary C.A.
Published: August 2019

Nonlinear effects are attributed to the dependence of the susceptibility on the electric field, which becomes important at high field strengths, in optical fibers impose different limitations on the communications link, and an understanding of such effects is almost a prerequisite for actual light wave system designers. On the other hand, they offer a variety of possibilities for all-optical signal processing, amplification and regeneration, in the nonlinear regime, is introduced and shows the influence and consequences of the nonlinear effects of the propagation Gaussian pulse in photonic crystal fibers. In this paper, one reviews the effects - both detrimental and potentially beneficial - of optical nonlinearities in photonic crystal fibers.
Underwater Image Enhancement using Colour Restoration based on YCbCr Colour Model
Authors: kareem Hana H. , Daway Hazim G. , Daway Esraa G.
Published: August 2019

In this study, improvement of underwater images via colour re-correction was performed by designing a new method that uses colour restoration based on the integrated colour model with Rayleigh distribution (CRBICMRD). The proposed method was utilised for colour restoration in an image in the RGB model and for colour transformation in YCbCr space, where it processed the Y component. The integrated colour model with Rayleigh distribution was applied. Quantitative analyses indicated that the proposed method outperformed the multi-scale retinex algorithm with colour restoration, unsupervised colour correction method and Rayleigh stretching and averaging image planes by calculating no-reference-image quality assessments. Results indicated that CRBICMRD performed considerably better than the other methods in enhancing underwater images.
Simple Laboratory Test Utilization Interventions to Reduce Inappropriate Specialty Coagulation Testing
Authors: Huang Huiya , Cunningham Ashley M , Harrington Alexandra M
Published: August 2019

Objectives

The naming convention in coagulation may cause confusion in electronic ordering systems, leading to inappropriate test orders. We implemented test utilization efforts and studied utilization before and after interventions for two specialty coagulation assays.

Methods

Two interventions were implemented: test names were changed from factor assay to activity, and residents reviewed all factor V and X requests. A retrospective review of factor V and X activity orders was performed for the period 1 year before and after interventions.

Results

After interventions, factor V and X activity orders decreased by approximately 40%. Resulted tests decreased by 53.8% and 47.8%, corresponding to reductions of $2,493.05 and $1,867.80 per year in laboratory charges for factor V and factor X activity, respectively. Abnormal factor V activity results increased from 45% to 59%. Factor V activity orders from outpatient clinics decreased by 21.6%.

Conclusions

Simple interventions can reduce inappropriate specialty coagulation test orders and unnecessary costs.
Hybrid modelling of biological systems using fuzzy continuous Petri nets
Authors: Liu Fei , Sun Wujie , Heiner Monika , Gilbert David
Published: August 2019

Integrated modelling of biological systems is challenged by composing components with sufficient kinetic data and components with insufficient kinetic data or components built only using experts’ experience and knowledge. Fuzzy continuous Petri nets (FCPNs) combine continuous Petri nets with fuzzy inference systems, and thus offer an hybrid uncertain/certain approach to integrated modelling of such biological systems with uncertainties. In this paper, we give a formal definition and a corresponding simulation algorithm of FCPNs, and briefly introduce the FCPN tool that we have developed for implementing FCPNs. We then present a methodology and workflow utilizing FCPNs to achieve hybrid (uncertain/certain) modelling of biological systems illustrated with a case study of the Mercaptopurine metabolic pathway. We hope this research will promote the wider application of FCPNs and address the uncertain/certain integrated modelling challenge in the systems biology area.
pWGBSSimla: a profile-based whole-genome bisulfite sequencing data simulator incorporating methylation QTLs, allele-specific methylations and differentially methylated regions
Authors: Chung Ren-Hua , Kang Chen-Yu
Published: August 2019

Motivation

DNA methylation plays an important role in regulating gene expression. DNA methylation is commonly analyzed using bisulfite sequencing (BS-seq)-based designs, such as whole-genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS) and oxidative bisulfite sequencing (oxBS-seq). Furthermore, there has been growing interest in investigating the roles that genetic variants play in changing the methylation levels (i.e. methylation quantitative trait loci or meQTLs), how methylation regulates the imprinting of gene expression (i.e. allele-specific methylation or ASM) and the differentially methylated regions (DMRs) among different cell types. However, none of the current simulation tools can generate different BS-seq data types (e.g. WGBS, RRBS and oxBS-seq) while modeling meQTLs, ASM and DMRs.

Results

We developed profile-based whole-genome bisulfite sequencing data simulator (pWGBSSimla), a profile-based bisulfite sequencing data simulator, which simulates WGBS, RRBS and oxBS-seq data for different cell types based on real data. meQTLs and ASM are modeled based on the block structures of the methylation status at CpGs, whereas the simulation of DMRs is based on observations of methylation rates in real data. We demonstrated that pWGBSSimla adequately simulates data and allows performance comparisons among different methylation analysis methods.

Availability and implementation

pWGBSSimla is available at https://omicssimla.sourceforge.io.

Supplementary information

Supplementary data are available at Bioinformatics online.
Latitudinal and altitudinal variation in ecologically important traits in a widespread butterfly
Authors: Günter Franziska , Beaulieu Michaël , Brunetti Massimo , Lange Lena , Schmitz Ornés Angela , Fischer Klaus
Published: August 2019

Understanding how organisms adapt to complex environments lies at the very heart of evolutionary biology and ecology, and is of particular concern in the current era of anthropogenic global change. Variation in ecologically important traits associated with environmental gradients is considered to be strong evidence for adaptive responses. Here, we study phenotypic variation along a latitudinal and an altitudinal cline in 968 field-collected males of the widespread European butterfly Pieris napi. In contrast to our expectations, body size decreased with increasing latitude and altitude, suggesting that warmer rather than cooler conditions may be more beneficial for individual development in this species. Higher altitudes but not latitudes seemed to be associated with increased flight performance, suggesting stronger challenges for flight activity in high-altitude environments (e.g. due to strong wind). Moreover, wing melanization increased while yellow reflectance decreased towards colder environments in both clines. Thus, increased melanization under thermally challenging conditions seems to compromise investment into a sexually selected trait, resulting in a trade-off. Our study, although exclusively based on field-collected males, revealed indications of adaptive patterns along geographical clines. It documents the usefulness of field-collected specimens, and the strength of comparing latitudinal and altitudinal clines to identify traits being potentially under thermal selection.
Improving the Integration of Restoration and Conservation in Marine and Coastal Ecosystems: Lessons from the Deepwater Horizon Disaster
Authors: Wallace Richard L , Gilbert Sherryl , Reynolds John E
Published: August 2019

In the wake of the Deepwater Horizon disaster, much has been learned about the biological, ecological, physical, and chemical conditions of the Gulf of Mexico. In parallel, the research community has also gained insight about the social and organizational structures and processes necessary for oil spill response and subsequent marine and coastal restoration. However, even with these lessons from both the Deepwater Horizon and previous spills, including 1989’s Exxon Valdez and the Ixtoc 1 in 1979, our understanding of how to avoid future crises has not advanced at the same pace as offshore oil and gas development. We argue that this progress deficit indicates a continued devaluing of marine and coastal resources. We believe that we must, instead, advance a proactive conservation ethic based on the precautionary principle and an appropriately placed burden of proof—strategies that will help reduce our reliance on costly restoration and protect marine and coastal ecosystems.
Prenatal Exposure to Ethanol Alters Synaptic Activity in Layer V/VI Pyramidal Neurons of the Somatosensory Cortex
Authors: Delatour Laurie C , Yeh Pamela W L , Yeh Hermes H
Published: August 2019

Fetal alcohol spectrum disorder (FASD) encompasses a range of cognitive and behavioral deficits, with aberrances in the function of cerebral cortical pyramidal neurons implicated in its pathology. However, the mechanisms underlying these aberrances, including whether they persist well beyond ethanol exposure in utero, remain to be explored. We addressed these issues by employing a mouse model of FASD in which pregnant mice were exposed to binge-type ethanol from embryonic day 13.5 through 16.5. In both male and female offspring (postnatal day 28–32), whole-cell patch clamp recording of layer V/VI somatosensory cortex pyramidal neurons revealed increases in the frequency of excitatory and inhibitory postsynaptic currents. Furthermore, expressing channelrhodopsin in either GABAergic interneurons (Nkx2.1Cre-Ai32) or glutamatergic pyramidal neurons (Emx1IRES Cre-Ai32) revealed a shift in optically evoked paired-pulse ratio. These findings are consistent with an excitatory-inhibitory imbalance with prenatal ethanol exposure due to diminished inhibitory but enhanced excitatory synaptic strength. Prenatal ethanol exposure also altered the density and morphology of spines along the apical dendrites of pyramidal neurons. Thus, while both presynaptic and postsynaptic mechanisms are affected following prenatal exposure to ethanol, there is a prominent presynaptic component that contributes to altered inhibitory and excitatory synaptic transmission in the somatosensory cortex.
Genomic Characterization of Recent and Historic Meningococcal Serogroup E Invasive Disease in Australia: A Case Series
Authors: Thangarajah Dharshi , Guglielmino Christine J D , Lambert Stephen B , Khandaker Gulam , Vasant Bhakti R , Malo Jonathan A , Smith Helen V , Jennison Amy V
Published: August 2019

We report the recent emergence of invasive meningococcal disease due to serogroup E in Queensland, Australia, in previously healthy patients. Molecular typing revealed the genotype of these strains to be E:P1.21-7,16:F5-36:ST-1157 (cc1157); when analyzed phylogenetically, compared with international cc1157 strains, they were relatively unrelated to each other.
Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9
Authors: Jang Hyun-Duk , Lee Sang Eun , Yang Jimin , Lee Hyun-Chae , Shin Dasom , Lee Hwan , Lee Jaewon , Jin Sooryeonhwa , Kim Soungchan , Lee Seung Ji , You Jihye , Park Hyun-Woo , Nam Ky-Youb , Lee Sang-Hak , Park Sahng Wook , Kim Jin-Soo , Kim Sang-Yeob , Kwon Yoo-Wook , Kwak Soo Heon , Yang Han-Mo , Kim Hyo-Soo
Published: August 2019

Aims

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels.

Methods and results

The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1.

Conclusion

We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.
Validation of self-reported help-seeking, and measurement of the patient interval, for cancer symptoms: an observational study to inform methodological challenges in symptomatic presentation research
Authors: Smith Sarah M , Whitaker Katriina L , Cardy Amanda H , Elliott Alison M , Hannaford Philip C , Murchie Peter
Published: August 2019

Background

To improve earlier presentation with potential symptoms of cancer, accurate data are needed on how people respond to these symptoms. It is currently unclear how self-reported medical help-seeking for symptoms associated with cancer by people from the community correspond to what is recorded in their general practice records, or how well the patient interval (time from symptom onset to first presentation to a health-professional) can be estimated from patient records.

Method

Data from two studies that reviewed general practice electronic records of residents in Scotland, (i) the ‘Useful Study’: respondents to a general population survey who reported experiencing symptoms potentially associated with one of four common cancers (breast, colorectal, lung and upper gastro-intestinal) and (ii) the ‘Detect Cancer Early’ programme: cancer patients with one of the same four cancers. Survey respondents’ self-reported help-seeking (yes/no) was corroborated; Cohen’s Kappa assessed level of agreement. Combined data on the patient interval were evaluated using descriptive analysis.

Results

‘Useful Study’ respondents’ self-report of help-seeking showed exact correspondence with general practice electronic records in 72% of cases (n = 136, kappa 0.453, moderate agreement). Between both studies, 1269 patient records from 35 general practices were reviewed. The patient interval could not be determined in 44% (n = 809) of symptoms presented by these individuals.

Conclusions

Patient self-report of help-seeking for symptoms potentially associated with cancer offer a reasonably accurate method to research responses to these symptoms. Incomplete patient interval data suggest routine general practice records are unreliable for measuring this important part of the patient’s symptom journey.
Effects of module truncation on biochemical characteristics and products distribution of a new alginate lyase with two catalytic modules
Authors: Hu Fu , Li Qian , Zhu Benwei , Ni Fang , Sun Yun , Yao Zhong
Published: August 2019

In this work, we investigated the functions of structural modules within alginate lyase by truncating an endo-type alginate lyase into two successive catalytic modules. The effects of module deletion on biochemical characteristics and product distributions were further investigated. The N-terminal module (Aly7B-CDI) exhibited no activity toward alginate, polyM or polyG, but the C-terminal module (Aly7B-CDII) retained its activity. The full-length enzyme (Aly7B) and its truncated counterpart (Aly7B-CDII) had similar substrate specificities, but Aly7B-CDII had lower activity. Moreover, the activity of Aly7B was much higher than Aly7B-CDII at 30°C. Aly7B-CDII, however, possessed higher optimal pH and better pH stability than the full-length enzyme. The final degradation products for Aly7B were unsaturated di-, tri- and tetra-oligosaccharides, and those for Aly7B-CDII were unsaturated mono-, di-, tri-, tetra- and penta-oligosaccharides. Therefore, the potential impact of the noncatalytic module Aly7B-CDI on the catalytic module Aly7B-CDII was further elucidated by characterizing Aly7B and its truncations. These data contribute to the functional understanding of these differing modules.
Induction and Kinetics of Complement-Fixing Antibodies Against Plasmodium vivax Merozoite Surface Protein 3α and Relationship With Immunoglobulin G Subclasses and Immunoglobulin M
Authors: Oyong Damian A , Wilson Danny W , Barber Bridget E , William Timothy , Jiang Jianlin , Galinski Mary R , Fowkes Freya J I , Grigg Matthew J , Beeson James G , Anstey Nicholas M , Boyle Michelle J
Published: August 2019

Complement-fixing antibodies targeting Plasmodium vivax merozoite surface protein 3α are prevalent in both children and adults with infection, with both immunoglobulin G and M mediating complement fixation. Magnitudes of complement-fixing antibodies are influenced by antigenic region.
The Causes and Effects of Leaks in International Negotiations
Authors: Castle Matthew , Pelc Krzysztof J
Published: August 2019

International negotiations are founded on secrecy. Yet, unauthorized leaks of negotiating documents have grown common. What are the incentives behind leaks, and what are their effects on bargaining between states? Specifically, are leaks offensive or defensive: are they intended to spur parties to make more ambitious commitments, or are they more often intended to claw back commitments made? We examine these questions in the context of trade negotiations, the recurring form of which affords us rare empirical traction on an otherwise elusive issue. We assemble the first dataset of its kind, covering 120 discrete leaks from 2006 to 2015. We find that leaks are indeed rising in number. Leaks are clustered around novel legal provisions and appear to be disproportionately defensive: they serve those actors intent on limiting commitments made. The European Union (EU) appears responsible for the majority of leaks occurring worldwide. Using party manifesto data to track changing ideological positions within the EU, we find that the occurrence of leaks correlates with opposition to economic liberalization within the average EU political party. Moreover, leaks appear effective in shifting public debate. We examine trade officials’ internal communications and media coverage in the wake of a specific leak of negotiations between Canada and the EU. A given negotiating text attracts more negative coverage when it is leaked than when the same text is officially released. In sum, political actors leak information strategically to mobilize domestic audiences toward their preferred negotiating outcome.
Tubulin detyrosination promotes human trophoblast syncytium formation
Authors: Wang Rui , Yu Ruoxuan , Zhu Cheng , Lin Hai-Yan , Lu Xiaoyin , Wang Hongmei
Published: August 2019

Human trophoblast syncytialization is one of the most important yet least understood events during placental development. In this study, we found that detyrosinated α-tubulin (detyr-α-tub), which is negatively regulated by tubulin tyrosine ligase (TTL), was elevated during human placental cytotrophoblast fusion. Correspondingly, relatively high expression of TTL protein was observed in first-trimester human placental cytotrophoblast cells, but fusing trophoblast cells exhibited much lower levels of TTL. Notably, fusion of preeclamptic cytotrophoblast cells was compromised but could be partially rescued by knockdown of TTL levels. Mechanistically, chronic downregulation of TTL in trophoblast cells resulted in significantly elevated expression of detyr-α-tub. Restoration of detyr-α-tub thus contributed to the cell surface localization of the fusogenic protein Syncytin-2 and the gap junction protein Connexin 43 (Cx43), which in turn promoted successful fusion between trophoblast cells. Taken together, the results suggest that tubulin detyrosination plays an essential role in human trophoblast fusogenic protein aggregation and syncytialization. Insufficient tubulin detyrosination leads to defects in syncytialization and potentially to the onset of preeclampsia.
Microbiological and clinical characteristics of cryptococcemia: a retrospective analysis of 85 cases in a Chinese hospital
Authors: Fu Yiqi , Xu Min , Zhou Hua , Yao Yake , Zhou Jianying , Pan Zhijie
Published: August 2019

Cryptococcemia is a life-threatening fungal infection. Sometimes, it is hard to diagnose. The studies to describe the characteristics of cryptococcemia specifically were limited. We performed this retrospective analysis in a Chinese hospital during 2002–2015, including 85 cryptococcemia cases and 52 Cryptococcus spp. isolates. The species, mating type, antifungal susceptibility and multilocus sequence typing of Cryptococcus spp. were determined. C. neoformans var. grubii MATα of sequence type (ST) 5 is the representative strain of cryptococcemia, accounting for 51 isolates. The MIC50/90 values were 0.5/0.5, 1.0/1.0, 2.0/4.0, ≤0.06/0.25, and ≤0.06/≤0.06 μg/ml for amphotericin B, flucytosine, fluconazole, itraconazole, and voriconazole, respectively. Cryptococcemia was the first diagnostic proof of cryptococcosis in 37 patients (43.5%, 37/85). Compared with the patients initially diagnosed of cryptococcosis in other sites (mainly cerebrospinal fluid), the patients firstly diagnosed by blood culture had prolonged time from admission to diagnosis of cryptococcosis (9 days vs. 2 days, P < .001) and higher 30-day mortality (54.1% vs. 20.8%, P = .003), while fewer symptoms of meningitis (45.9% vs. 100%, P < .001). For the patients receiving lumbar puncture, the occurrence of meningitis was similar between the patients firstly diagnosed by blood culture and those firstly diagnosed in other sites (94.1% vs. 100%, P = .26). However, the patients first diagnosed by blood culture had lower baseline intracranial pressure (250 mm H2O vs. 342.5 mm H2O, P = .001). In conclusion, patients with cryptococcemia as the first diagnostic proof of cryptococcosis usually had neglected subtle symptoms of meningitis, which may result in delayed diagnosis and catastrophic outcome.
Broad-lined type Ic supernova iPTF16asu: A challenge to all popular models
Authors: Wang L J , Wang X F , Cano Z , Wang S Q , Liu L D , Dai Z G , Deng J S , Yu H , Li B , Song L M , Qiu Y L , Wei J Y
Published: August 2019

It is well known that ordinary supernovae (SNe) are powered by 56Ni cascade decay. Broad-lined type Ic SNe (SNe Ic-BL) are a subclass of SNe that are not all exclusively powered by 56Ni decay. It was suggested that some SNe Ic-BL are powered by magnetar spin-down. iPTF16asu is a peculiar broad-lined type Ic supernova discovered by the intermediate Palomar Transient Factory. With a rest-frame rise time of only 4 d, iPTF16asu challenges the existing popular models, for example, the radioactive heating (56Ni-only) and the magnetar +56Ni models. Here we show that this rapid rise could be attributed to interaction between the SN ejecta and a pre-existing circumstellar medium ejected by the progenitor during its final stages of evolution, while the late-time light curve can be better explained by energy input from a rapidly spinning magnetar. This model is a natural extension to the previous magnetar model. The mass-loss rate of the progenitor and ejecta mass are consistent with a progenitor that experienced a common envelope evolution in a binary. An alternative model for the early rapid rise of the light curve is the cooling of a shock propagating into an extended envelope of the progenitor. It is difficult at this stage to tell which model (interaction+magnetar + 56Ni or cooling+magnetar + 56Ni) is better for iPTF16asu. However, it is worth noting that the inferred envelope mass in the cooling+magnetar + 56Ni is very high.
Cosmological filaments in the light of excursion set of saddle points
Authors: Fard Mohammad Ansari , Taamoli Sina , Baghram Shant
Published: August 2019

The universe in large scales is structured as a network known as cosmic web. Filaments are one of the structural components of this web, which can be introduced as a novel probe to study the formation and evolution of structures and as a probe to study the cosmological models and to address the missing baryon problem. The aim of this work is to introduce an analytical framework to study the statistics of filaments such as number density of them and also to obtain the length-mass relation. For this objective, we model filaments as collapsed objects which have an extension in one direction, accordingly we use the ellipsoidal collapse to study the evolution of an over-dense region via gravitational instability. We find that the non-linear density of filaments in the epoch of formation is almost mass independent and is in order of ∼30. By introducing filament’s extended condition, we find a fitting function for length-mass relation. For the statistics of filaments, we propose a novel framework named excursion set of saddle points. In this approach, we count the saddle points of the density field Hessian matrix, and relate it to the count of filaments. In addition, we addressed the filament in filament problem with up-crossing approximation.
DSA-10: a prototype array for localizing fast radio bursts
Authors: Kocz J , Ravi V , Catha M , D’Addario L , Hallinan G , Hobbs R , Kulkarni S , Shi J , Vedantham H , Weinreb S , Woody D
Published: August 2019

The Deep Synoptic Array 10-dish prototype (DSA-10) is an instrument designed to detect and localize fast radio bursts with arcsecond accuracy in real time. Deployed at Owens Valley Radio Observatory, it consists of ten 4.5-m diameter dishes, equipped with a 250-MHz bandwidth dual polarization receiver, centred at 1.4 GHz. The 20 input signals are digitized and field programmable gate arrays are used to transform the data to the frequency domain and transmit it over ethernet. A series of computer servers buffer both raw data samples and perform a real time search for fast radio bursts on the incoherent sum of all inputs. If a pulse is detected, the raw data surrounding the pulse are written to disc for coherent processing and imaging. The prototype system was operational from 2017 June to 2018 February conducting a drift scan search. Giant pulses from the Crab Pulsar were used to test the detection and imaging pipelines. The 10-dish prototype system was brought online again in 2019 March, and will gradually be replaced with the new DSA-110, a 110-dish system, over the next 2 yr to improve sensitivity and localization accuracy.
Dark-ages reionization and galaxy formation simulation – XVI. The thermal memory of reionization
Authors: Davies James E , Mutch Simon J , Qin Yuxiang , Mesinger Andrei , Poole Gregory B , Wyithe J Stuart B
Published: August 2019

Intergalactic medium temperature is a powerful probe of the epoch of reionization, as information is retained long after reionization itself. However, mean temperatures are highly degenerate with the timing of reionization, with the amount heat injected during the epoch, and with the subsequent cooling rates. We post-process a suite of semi-analytic galaxy formation models to characterize how different thermal statistics of the intergalactic medium can be used to constrain reionization. Temperature is highly correlated with redshift of reionization for a period of time after the gas is heated. However as the gas cools, thermal memory of reionization is lost, and a power-law temperature–density relation is formed, T = T0(1 + δ)1 − γ with γ ≈ 1.5. Constraining our model against observations of electron optical depth and temperature at mean density, we find that reionization likely finished at $z_{\rm {reion}} = 6.8 ^{+ 0.5} _{-0.8}$ with a soft spectral slope of $\alpha = 2.8 ^{+ 1.2} _{-1.0}$. By restricting spectral slope to the range [0.5, 2.5] motivated by population II synthesis models, reionization timing is further constrained to $z_{\rm {reion}} = 6.9 ^{+ 0.4} _{-0.5}$. We find that, in the future, the degeneracies between reionization timing and background spectrum can be broken using the scatter in temperatures and integrated thermal history.
Modelling the AGN broad line region using single-epoch spectra – I. The test case of Arp 151
Authors: Raimundo S I , Pancoast A , Vestergaard M , Goad M R , Barth A J
Published: August 2019

We show that individual (single-epoch) spectra of active galactic nuclei (AGNs) can constrain some of the geometry and dynamics of the AGN broad line region. Studies of the cosmic influence of supermassive black holes are limited by the current large uncertainties in the determination of black hole masses. One dominant limitation is the unknown geometry, dynamics, and line-of-sight inclination of the broad line region, used to probe the central black hole mass. Recent progress has been made to constrain the spatial and kinematic structure of the broad line region using dynamical modelling of AGN monitoring data and an underlying physical model for the broad line region. In this work we test the ability of a modified version of this dynamical modelling code to constrain the broad line region structure using single-epoch spectra. We test our modelling code on single-epoch spectra of nearby Arp 151 by comparing our results with those obtained with monitoring data of this same object. We find that a significant fraction of the broad line region parameters can indeed be adequately constrained, with uncertainties that are comparable to, or at most a factor of approximately a few higher than those obtained from modelling of monitoring data. Considering the wealth of available single-epoch spectroscopic observations, this method is promising for establishing the overall AGN population trends in the geometry and dynamics of the broad line region. This method can be applied to spectra of AGNs at low and high redshift making it valuable for studies of cosmological black hole and AGN evolution.
A year in the life of GW170817: the rise and fall of a structured jet from a binary neutron star merger
Authors: Troja E , van Eerten H , Ryan G , Ricci R , Burgess J M , Wieringa M H , Piro L , Cenko S B , Sakamoto T
Published: August 2019

We present the results of our year-long afterglow monitoring of GW170817, the first binary neutron star (NS) merger detected by advanced LIGO and advanced Virgo. New observations with the Australian Telescope Compact Array (ATCA) and the Chandra X-ray Telescope were used to constrain its late-time behavior. The broadband emission, from radio to X-rays, is well-described by a simple power-law spectrum with index β ∼0.585 at all epochs. After an initial shallow rise ∝ t0.9, the afterglow displayed a smooth turn-over, reaching a peak X-ray luminosity of LX≈5 ×1039 erg s−1 at 160 d, and has now entered a phase of rapid decline, approximately ∝ t−2. The latest temporal trend challenges most models of choked jet/cocoon systems, and is instead consistent with the emergence of a relativistic structured jet seen at an angle of ≈22○ from its axis. Within such model, the properties of the explosion (such as its blastwave energy EK ≈ 2 × 1050 erg, jet width θc ≈4○, and ambient density n ≈3 × 10−3 cm−3) fit well within the range of properties of cosmological short GRBs.
Machine learning and Kolmogorov analysis to reveal gravitational lenses
Authors: Mirzoyan S S , Khachatryan H , Yegorian G , Gurzadyan V G
Published: August 2019

We present an automated approach to detect and extract information from the astronomical data sets on the shapes of such objects as galaxies, star clusters and, especially, elongated ones such as the gravitational lenses. First, the Kolmogorov stochasticity parameter is used to retrieve the sub-regions that are worth further attention. Then we turn to image processing and machine learning Principal Component Analysis algorithm to retrieve the sought objects and reveal the information on their morphologies. We show the capability of our automated method to identify distinct objects and to classify them based on the input parameters. A catalogue of possible lensing objects is retrieved as an output of the software, then their inspection is performed for the candidates that survive the filters applied.
Evidence for C ii diffuse line emission at redshift z ∼ 2.6
Authors: Yang Shengqi , Pullen Anthony R , Switzer Eric R
Published: August 2019

C ii is one of the brightest emission lines from star-forming galaxies and is an excellent tracer for star formation. Recent work measured the C ii emission line amplitude for redshifts 2 < z < 3.2 by cross-correlating Planck High Frequency Instrument emission maps with tracers of overdensity from the Baryon Oscillation Spectroscopic Sky Survey, finding ${I}_{{\text C}\,\rm {\small II}}=6.6^{+5.0}_{-4.8}\times {10}^{4}$ Jy sr−1 at $95\,{\text{per cent}}$ confidence level. In this paper, we present a refinement of this earlier work by improving the mask weighting in each of the Planck bands and the precision in the covariance matrix. We report a detection of excess emission in the 545 GHz Planck band separate from the cosmic infrared background (CIB) present in the 353–857 GHz Planck bands. This excess is consistent with redshifted C ii emission, in which case we report $b_{{\text C} \,\rm {\small II}}I_{{\text C} \,\rm {\small II}} =2.0^{+1.2}_{-1.1}\times 10^5$ Jy sr−1 at $95\ {\text {per cent}}$ confidence level, which strongly favours many collisional excitation models of C ii emission. Our detection shows strong evidence for a model with a non-zero C ii parameter, though line intensity mapping observations at high spectral resolution will be needed to confirm this result.
The Evolution of Reverse Gyrase Suggests a Nonhyperthermophilic Last Universal Common Ancestor
Authors: Catchpole Ryan J , Forterre Patrick
Published: August 2019

Reverse gyrase (RG) is the only protein found ubiquitously in hyperthermophilic organisms, but absent from mesophiles. As such, its simple presence or absence allows us to deduce information about the optimal growth temperature of long-extinct organisms, even as far as the last universal common ancestor of extant life (LUCA). The growth environment and gene content of the LUCA has long been a source of debate in which RG often features. In an attempt to settle this debate, we carried out an exhaustive search for RG proteins, generating the largest RG data set to date. Comprising 376 sequences, our data set allows for phylogenetic reconstructions of RG with unprecedented size and detail. These RG phylogenies are strikingly different from those of universal proteins inferred to be present in the LUCA, even when using the same set of species. Unlike such proteins, RG does not form monophyletic archaeal and bacterial clades, suggesting RG emergence after the formation of these domains, and/or significant horizontal gene transfer. Additionally, the branch lengths separating archaeal and bacterial groups are very short, inconsistent with the tempo of evolution from the time of the LUCA. Despite this, phylogenies limited to archaeal RG resolve most archaeal phyla, suggesting predominantly vertical evolution since the time of the last archaeal ancestor. In contrast, bacterial RG indicates emergence after the last bacterial ancestor followed by significant horizontal transfer. Taken together, these results suggest a nonhyperthermophilic LUCA and bacterial ancestor, with hyperthermophily emerging early in the evolution of the archaeal and bacterial domains.
A deep learning genome-mining strategy for biosynthetic gene cluster prediction
Authors: Hannigan Geoffrey D , Prihoda David , Palicka Andrej , Soukup Jindrich , Klempir Ondrej , Rampula Lena , Durcak Jindrich , Wurst Michael , Kotowski Jakub , Chang Dan , Wang Rurun , Piizzi Grazia , Temesi Gergely , Hazuda Daria J , Woelk Christopher H , Bitton Danny A
Published: August 2019

Natural products represent a rich reservoir of small molecule drug candidates utilized as antimicrobial drugs, anticancer therapies, and immunomodulatory agents. These molecules are microbial secondary metabolites synthesized by co-localized genes termed Biosynthetic Gene Clusters (BGCs). The increase in full microbial genomes and similar resources has led to development of BGC prediction algorithms, although their precision and ability to identify novel BGC classes could be improved. Here we present a deep learning strategy (DeepBGC) that offers reduced false positive rates in BGC identification and an improved ability to extrapolate and identify novel BGC classes compared to existing machine-learning tools. We supplemented this with random forest classifiers that accurately predicted BGC product classes and potential chemical activity. Application of DeepBGC to bacterial genomes uncovered previously undetectable putative BGCs that may code for natural products with novel biologic activities. The improved accuracy and classification ability of DeepBGC represents a major addition to in-silico BGC identification.
Global prediction of chromatin accessibility using small-cell-number and single-cell RNA-seq
Authors: Zhou Weiqiang , Ji Zhicheng , Fang Weixiang , Ji Hongkai
Published: August 2019

Conventional high-throughput genomic technologies for mapping regulatory element activities in bulk samples such as ChIP-seq, DNase-seq and FAIRE-seq cannot analyze samples with small numbers of cells. The recently developed low-input and single-cell regulome mapping technologies such as ATAC-seq and single-cell ATAC-seq (scATAC-seq) allow analyses of small-cell-number and single-cell samples, but their signals remain highly discrete or noisy. Compared to these regulome mapping technologies, transcriptome profiling by RNA-seq is more widely used. Transcriptome data in single-cell and small-cell-number samples are more continuous and often less noisy. Here, we show that one can globally predict chromatin accessibility and infer regulatory element activities using RNA-seq. Genome-wide chromatin accessibility predicted by RNA-seq from 30 cells can offer better accuracy than ATAC-seq from 500 cells. Predictions based on single-cell RNA-seq (scRNA-seq) can more accurately reconstruct bulk chromatin accessibility than using scATAC-seq. Integrating ATAC-seq with predictions from RNA-seq increases the power and value of both methods. Thus, transcriptome-based prediction provides a new tool for decoding gene regulatory circuitry in samples with limited cell numbers.
TRLS-06. PHASE 1 EXPANSION STUDY OF IRINOTECAN LIPOSOME INJECTION (nal-IRI) IN PATIENTS WITH METASTATIC BREAST CANCER (mBC): FINDINGS FROM THE COHORT WITH ACTIVE BRAIN METASTASIS (BM)
Authors: Anders Carey , Munster Pamela , Northfelt Donald , Han Hyo Sook , Ma Cynthia , Maxwell Fiona , Wang Tiffany , Belanger Bruce , Zhang Bin , Moore Yan , Sachdev Jasgit C
Published: August 2019

BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.
THER-15. DEVELOPING TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELL THERAPY FOR BRAIN METASTASES
Authors: Mercer-Smith Alison , Jiang Wulin , Bago Juli , Khagi Simon , Anders Carey , Hingtgen Shawn
Published: August 2019

INTRODUCTION: Non-small cell lung cancer (NSCLC) and breast cancer are the most common cancers that metastasize to the brain. New therapies are needed to seek out and eradicate metastases. Genetically engineered neural stem cells (NSCs) have shown unique tumor-homing capacity, allowing them to deliver cytotoxic proteins directly to tumors. An ideal NSC drug carrier would be readily available and autologous. We have transdifferentiated human fibroblasts into induced NSCs (hiNSCs) that home to tumors and engineered the hiNSCs to release the cytotoxic protein TRAIL. Here we used intracerebroventricular (ICV) injections to deliver hiNSCs to metastatic foci. METHODS: We performed an in vitro efficacy co-culture assay, used in vivo studies to determine the migration, persistence, and efficacy of therapeutic hiNSCs against H460 NSCLC and triple-negative breast cancer MB231-Br tumors in the brain. Following the establishment of tumors in the brains of nude mice, hiNSCs were injected directly into the tumor or the ventricle contralateral to the site of tumor. The migration and persistence of hiNSCs was investigated by following the bioluminescence of the hiNSCs. The therapeutic efficacy of the hiNSCs was determined by following the bioluminescece of the tumor. RESULTS/CONCLUSION: Co-culture results demonstrated that hiNSC therapy reduced the viability of H460 and MB231-Br up to 75% and 99.8% respectively compared to non-treated controls. ICV-administered hiNSC serial imaging show that cells persisted for more than one week. Fluorescent analysis of tissue sections showed that hiNSCs co-localized with lateral and a contralateral tumors within 7 days. Using H460 and MB231-Br models, kinetic tracking of intracranial tumor volumes showed intratumoral or ICV-injected therapeutic hiNSCs reduced the growth rate of brain tumors by 31-fold and 3-fold, respectively. This work demonstrates for the first time that we can effectively deliver personalized cytotoxic tumor-homing cells through the ventricles to target brain metastases.
MLTI-16. SYSTEMIC THERAPY FOLLOWING CRANIOTOMY IN PATIENTS WITH A SOLITARY BREAST CANCER BRAIN METASTASIS
Authors: Hulsbergen Alexander , Cho Logan , Mammi Marco , Lamba Nayan , Smith Timothy , Broekman Marike , Lin Nancy
Published: August 2019

INTRODUCTION: Between 15–50% of patients with metastatic breast cancer will develop brain metastases, with the frequency more common in patients with HER2-positive or triple-negative subtypes. Surgical resection is often indicated for diagnostic and/or therapeutic intent for patients presenting with a solitary lesion and/or symptomatic lesion(s) with mass effect. Practice patterns and patient outcomes with respect to the use of postoperative systemic therapy (ST) after resection of a solitary breast cancer brain metastasis (BCBM) have not been previously well-described, particularly in the modern era. METHODS: A multi-institutional retrospective review of 44 patients was performed to assess the impact of types of ST on site of recurrence, progression-free survival (PFS) and overall survival (OS) after resection of solitary BCBM. RESULTS: Stratified estimated survival was 15, 24 and 23 months for patients with triple negative, estrogen receptor positive (ER+), and human epidermal growth factor receptor 2 positive (HER2+) BCBMs. Patients receiving postoperative ST had a longer median PFS (8 versus 4 months) and OS (32 versus 15 months). Nine patients (20%) had extracranial progression, 23 (52%) had intracranial progression, three (8%) had both, and nine (20%) did not experience progression at last follow-up. Multivariate analysis showed that postoperative hormonal therapy was associated with longer OS in estrogen receptor (ER) positive patients (HR = 0.26; CI = 0.08 – 0.89; p = 0.03), but not with longer PFS. Postoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy was not associated with longer PFS or OS in HER2+ patients. CONCLUSIONS: Disease progression occurred intracranially more often than extracranially following resection of a solitary BCBM. In ER+ patients, postoperative hormonal therapy was associated with longer OS. Postoperative HER2-targeted therapy did not show survival benefits in HER2+ patients. These results should be validated in larger cohorts.
OTHR-11. TUMOR RELATED IMPAIRMENTS OF NEUROCOGNITIVE FUNCTIONS IN PATIENTS WITH BRAIN METASTASES
Authors: Zhen Junjie , Li Shaoqun , Wen Lei , Peng Zhangrui , Lai Mingyao , Zhou Cheng , Cai Linbo
Published: August 2019

OBJECTIVE: To study whether the neurocognitive functions were affected by brain metastases in patients, and what are the potential risk factors. METHODS: A total of 172 patients with brain metastases were retrospectively analyzed. Prior to radiotherapy of brain metastases, the neurocognitive function was evaluated by a wide range of tests including MOCA, VFT, HVLT-R, TMT-A, TMT-B and TOL. Kappa test was used to analyze the consistency of physical examination and neurocognitive assessment results. The related factors were analyzed with univariate and multivariate analysis. RESULTS: 53 out of 172 patients (30.8%) were identified with cognitive impairments by physical examination. The assessment with neurocognitive scales revealed that there were 148 cases of cognitive impairment (86.0%) and 24 cases of normal cognition (14.0%). Kappa=0.025, indicating that the difference between neurocognitive assessment results and physical examination was significant. The univariate analysis on the factors related to neurocognitive impairment revealed that the risk factors that may affect the neurocognitive functions included age, KPS, m-GPA score, RPA classification, whether the original tumor was under control, with or without brain metastases. After adjusting for education, the multivariate analysis showed that age≥45 years old, KPS≤70, RPA classification >2 and m-GPA score< 3 were independent risk factors for neurocognitive impairment. CONCLUSION: Patients with brain metastases were found to have various degrees of neurocognitive impairment prior to radiotherapy. The neurocognitive functions of patients can be more precisely evaluated by a comprehensive scale assessment. Age, KPS, RPA classification and m-GPA score are the main factors associated with neurocognitive impairment.