bluuebunny/crossref_metadata_2025 huggingface dataset:
You get what you screen for: on the value of fermentation characterization in high-throughput strain improvements in industrial settings
Authors: Wehrs Maren , de Beaumont-Felt Alexander , Goranov Alexi , Harrigan Patrick , de Kok Stefan , Lieder Sarah , Vallandingham Jim , Tyner Kristina
Published: August 2020

While design and high-throughput build approaches in biotechnology have increasingly gained attention over the past decade, approaches to test strain performance in high-throughput have received less discussion in the literature. Here, we describe how fermentation characterization can be used to improve the overall efficiency of high-throughput DBTAL (design-build-test-analyze-learn) cycles in an industrial context. Fermentation characterization comprises an in-depth study of strain performance in a bioreactor setting and involves semi-frequent sampling and analytical measurement of substrates, cell densities and viabilities, and (by)products. We describe how fermentation characterization can be used to (1) improve (high-throughput) strain design approaches; (2) enable the development of bench-scale fermentation processes compatible with a wide diversity of strains; and (3) inform the development of high-throughput plate-based strain testing procedures for improved performance at larger scales.
Echocardiographic photorealistic imaging of leiomyomatosis intravascularis
Authors: Czub Paweł , Budnik Monika , Majstrak Franciszek , Kochanowski Janusz , Hendzel Piotr , Opolski Grzegorz
Published: August 2020

We present a case of patient with leiomyomatosis intravascularis. To diagnose, we used 3D photorealistic imaging which allowed us better visualisation of pathological structures as well as planning the surgical procedure in greater detail. The main advantage of this technique is the possibility to move the virtual light source and thus visualize the specific part of the heart.
A specialised delivery system for stratospheric sulphate aerosols: design and operation
Authors: Janssens M. , de Vries I. E. , Hulshoff S. J. ,   DSE 16-02
Published: August 2020

Temporary stratospheric aerosol injection (SAI) using sulphate compounds could help to mitigate some of the adverse and irreversible impacts of global warming. Among the risks and uncertainties of SAI, the development of a delivery system presents an appreciable technical challenge. Early studies indicate that specialised aircraft appear the most feasible (McClelan et al., Aurora Flight Sciences, 2010; Smith and Wagner, Environ Res Lett 13(12), 2018). Yet, their technical design characteristics, financial cost of deployment, and emissions have yet to be studied in detail. Therefore, these topics are examined in this two- part study. This first part outlines a set of injection scenarios and proposes a detailed, feasible aircraft design. Part 2 considers the resulting financial cost and equivalent CO2 emissions spanned by the scenarios and aircraft. Our injection scenarios comprise the direct injection of H2SO4 vapour over a range of possible dispersion rates and an SO2 injection scenario for comparison. To accommodate the extreme demands of delivering large payloads to high altitudes, a coupled optimisation procedure is used to design the system. This results in an unmanned aircraft configuration featuring a large, slender, strut-braced wing and four custom turbofan engines. The aircraft is designed to carry high-temperature H2SO4, which is evaporated prior to injection into a single outboard engine plume. Optimised flight profiles are produced for each injection scenario, all involving an initial climb to an outgoing dispersion leg at 20 km altitude, followed by a return dispersion leg at a higher altitude of 20.5 km. All the scenarios considered are found to be technologically and logistically attainable. However, the results demonstrate that achieving high engine plume dispersion rates is of principal importance for containing the scale of SAI delivery systems based on direct H2SO4 injection, and to keep these competitive with systems based on SO2 injection.
The Benefit-Cost Ratio as a Decision Criteria When Managing Catastrophes
Authors: Aurland-Bredesen Kine Josefine
Published: August 2020

Previous work has shown that when projects are non-marginal, it creates an interdependence among projects. This implies that policies to manage catastrophes should not be evaluated in isolation but in conjunction with each other. As long as relative risk aversion is sufficiently high, the benefits of averting one catastrophe depend positively on the background risk created by other catastrophes. This specific bias makes it possible to create upper and lower boundaries on the willingness to pay to manage catastrophes and the optimal policy. These boundaries can be used to make inferences on which catastrophes should be averted and not, and in which order. The upper and lower boundaries depend only on the individual catastrophe’s benefit-cost ratio and the coefficient of risk aversion, which both are easy to identify using standard economic frameworks.
Cylindrocladiella peruviana and Pleiocarpon algeriense causing stem and crown rot on avocado (Persea americana)
Authors: Aiello Dalia , Gusella Giorgio , Vitale Alessandro , Guarnaccia Vladimiro , Polizzi Giancarlo
Published: August 2020

During the winter of 2018, 3-years-old trees of avocado (Persea americana) cv “Hass” from Trapani province (Sicily, Italy) showed symptoms of stem and crown rot. Two different fungi were consistently isolated from infected tissues. Morphological characterization and multi-locus phylogenies using five genomic loci (ITS, tef1, tub2, his3, and rpb2) identified these fungi as Cylindrocladiella peruviana and Pleiocarpon algeriense. Pathogenicity tests on healthy 5-months-old seedlings and 3-year-old trees of avocado reproduced similar symptoms as those observed in nature, and Koch’s postulates were fulfilled for both pathogens. Moreover, the tested fungal isolates revealed a different pathogenic behaviour among two species. Two isolates of Pleiocarpon algeriense resulted more aggressive than Cylindrocladiella peruviana isolates causing major lesions on young seedlings. This study is the first to report of stem and crown rot on avocado caused by Cylindrocladiella peruviana and Pleiocarpon algeriense.
The development of a multiplex PCR assay for the detection of Fusarium oxysporum f. sp. cubense lineage VI strains in East and Central Africa
Authors: Ndayihanzamaso P. , Karangwa P. , Mostert D. , Mahuku G. , Blomme G. , Beed F. , Swennen R. , Viljoen A.
Published: August 2020

Banana is a staple food and cash crop grown in East and Central Africa (ECA). The main banana varieties grown in ECA are the East African highland bananas (EAHB), although dessert/beer bananas such as Sukari Ndizi, Kayinja (Pisang Awak) and Gros Michel are also produced due to their high value at local markets. The Fusarium wilt fungus Fusarium oxysporum f. sp. cubense (Foc) causes disease of susceptible dessert/beer bananas, which significantly reduces yields. Banana Fusarium wilt is managed by excluding the pathogen from disease-free areas and by planting disease-resistant varieties in infested fields. Six phylogenetically closely-related vegetative compatibility groups (VCGs) of Foc, VCGs 0124, 0125, 0128, 01212, 01220 and 01222 are present in ECA, which all group together in Foc Lineage VI. Rapid and accurate detection of Foc Lineage VI strains is thus important to prevent its spread to disease-free areas. In this study, molecular markers specific to Foc Lineage VI were therefore developed. Primer sets were then combined in a multiplex PCR assay, and validated on a worldwide population of 623 known Foc isolates, other formae speciales and non-pathogenic Fusarium oxysporum isolates. The Foc Lineage VI multiplex PCR was used to identify Foc isolates collected in banana fields at five locations in Uganda and Tanzania. Foc Lineage VI DNA was detected at a concentration as low as 0.1 ng/μl, both in the absence and presence of banana DNA, and can therefore be used as an accurate diagnostic tool for Foc Lineage VI strains.
Seed bank has the potential for re-colonising urban stormwater ponds after reconstruction
Authors: Lenzewski Nikola , Jensen Kai , Ludewig Kristin
Published: August 2020

Urban stormwater ponds are important for flood protection and provide habitat for plants and animals in heavily sealed cities. Little is known about the diversity of plants in urban stormwater ponds and the vegetation composition is often influenced by sowing and planting. We analysed the re-colonisation of the vegetation in an urban stormwater pond, which was reconstructed to improve water retention. Specifically, we studied if the soil seed bank has the potential for re-colonising the pond. We analysed the standing vegetation from the year before until 2 years after reconstruction of a stormwater pond in Hamburg, Germany. Further, we analysed the soil seed bank in the year before and in the second year after reconstruction of the stormwater pond. We found 74 species in the soil seed bank in 2015 and 2017 with Juncus spp. and Epilobium spp. being the most dominant taxa. Our results indicate that urban stormwater ponds have the potential for re-colonisation out of seed bank and, thus, sowing is not a necessary management action in the reconstruction process.
Agent-oriented Decision Support System for Business Processes Management with Genetic Algorithm Optimization: an Application in Healthcare
Authors: Sulis Emilio , Terna Pietro , Di Leva Antonio , Boella Guido , Boccuzzi Adriana
Published: August 2020

Agent-based approaches have been known to be appropriate as systems and methods in medical administration in recent years. The increased attention to processes led to the recent growth of Business Process Management discipline, which quite exclusively adopt discrete-event modeling and simulation. This paper proposes a medical agent-oriented decision support system to integrate the achievements from management science, agent-based modeling, and artificial intelligence. In particular, we performed a practical application concerning a hospital emergency department medical system. We adopt the widely used multi-agent programmable modeling environment NetLogo. First, we demonstrated the ability to perform a clear representation of healthcare processes where agents (i.e., patients and hospital staff) operate in a 3D environment. This model allows performing a traditional what-if scenario analysis. Second, we explore how performing intelligent management of patients by applying genetic algorithms to find the criteria for the selection process of the subjects in the admission procedure. The results are encouraging towards a more extensive application of agent-oriented methodologies in healthcare management.
Agent-based Modeling for Ontology-driven Analysis of Patient Trajectories
Authors: Calvaresi Davide , Schumacher Michael , Calbimonte Jean-Paul
Published: August 2020

Patients are often required to follow a medical treatment after discharge, e.g., for a chronic condition, rehabilitation after surgery, or for cancer survivor therapies. The need to adapt to new lifestyles, medication, and treatment routines, can produce an individual burden to the patient, who is often at home without the full support of healthcare professionals. Although technological solutions –in the form of mobile apps and wearables– have been proposed to mitigate these issues, it is essential to consider individual characteristics, preferences, and the context of a patient in order to offer personalized and effective support. The specific events and circumstances linked to an individual profile can be abstracted as a patient trajectory, which can contribute to a better understanding of the patient, her needs, and the most appropriate personalized support. Although patient trajectories have been studied for different illnesses and conditions, it remains challenging to effectively use them as the basis for data analytics methodologies in decentralized eHealth systems. In this work, we present a novel approach based on the multi-agent paradigm, considering patient trajectories as the cornerstone of a methodology for modelling eHealth support systems. In this design, semantic representations of individual treatment pathways are used in order to exchange patient-relevant information, potentially fed to AI systems for prediction and classification tasks. This paper describes the major challenges in this scope, as well as the design principles of the proposed agent-based architecture, including an example of its use through a case scenario for cancer survivors support.
Predicting rice phenotypes with meta and multi-target learning
Authors: Orhobor Oghenejokpeme I. , Alexandrov Nickolai N. , King Ross D.
Published: August 2020

The features in some machine learning datasets can naturally be divided into groups. This is the case with genomic data, where features can be grouped by chromosome. In many applications it is common for these groupings to be ignored, as interactions may exist between features belonging to different groups. However, including a group that does not influence a response introduces noise when fitting a model, leading to suboptimal predictive accuracy. Here we present two general frameworks for the generation and combination of meta-features when feature groupings are present. Furthermore, we make comparisons to multi-target learning, given that one is typically interested in predicting multiple phenotypes. We evaluated the frameworks and multi-target learning approaches on a genomic rice dataset where the regression task is to predict plant phenotype. Our results demonstrate that there are use cases for both the meta and multi-target approaches, given that overall, they significantly outperform the base case.
Improvement of a rivet geometry for the self-piercing riveting of high-strength steel and multi-material joints
Authors: Uhe Benedikt , Kuball Clara-Maria , Merklein Marion , Meschut Gerson
Published: August 2020

As a result of lightweight design, increased use is being made of high-strength steel and aluminium in car bodies. Self-piercing riveting is an established technique for joining these materials. The dissimilar properties of the two materials have led to a number of different rivet geometries in the past. Each rivet geometry fulfils the requirements of the materials within a limited range. In the present investigation, an improved rivet geometry is developed, which permits the reliable joining of two material combinations that could only be joined by two different rivet geometries up until now. Material combination 1 consists of high-strength steel on both sides, while material combination 2 comprises aluminium on the punch side and high-strength steel on the die side. The material flow and the stress and strain conditions prevailing during the joining process are analysed by means of numerical simulation. The rivet geometry is then improved step-by-step on the basis of this analysis. Finally, the improved rivet geometry is manufactured and the findings of the investigation are verified in experimental joining tests.
Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment
Authors: Braun Leah T. , Rubinstein German , Zopp Stephanie , Vogel Frederick , Schmid-Tannwald Christine , Escudero Montserrat Pazos , Honegger Jürgen , Ladurner Roland , Reincke Martin
Published: August 2020

Purpose

Recurrence after pituitary surgery in Cushing’s disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD.

Methods

We systematically screened the literature regarding recurrent and persistent Cushing’s disease using the MESH term Cushing’s disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review.

Results and conclusions

Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient.
A Novel Interaction of Translocator Protein 18 kDa (TSPO) with NADPH Oxidase in Microglia
Authors: Loth Meredith K. , Guariglia Sara R. , Re Diane B. , Perez Juan , de Paiva Vanessa Nunes , Dziedzic Jennifer L. , Chambers Jeremy W. , Azzam Diana J. , Guilarte Tomás R.
Published: August 2020

In the brain neuropil, translocator protein 18 kDa (TSPO) is a stress response protein that is upregulated in microglia and astrocytes in diverse central nervous system pathologies. TSPO is widely used as a biomarker of neuroinflammation in preclinical and clinical neuroimaging studies. However, there is a paucity of knowledge on the function(s) of TSPO in glial cells. In this study, we explored a putative interaction between TSPO and NADPH oxidase 2 (NOX2) in microglia. We found that TSPO associates with gp91phox and p22phox, the principal subunits of NOX2 in primary murine microglia. The association of TSPO with gp91phox and p22phox was observed using co-immunoprecipitation, confocal immunofluorescence imaging, and proximity ligation assay. We found that besides gp91phox and p22phox, voltage-dependent anion channel (VDAC) also co-immunoprecipitated with TSPO consistent with previous reports. When we compared lipopolysaccharide (LPS) stimulated microglia to vehicle control, we found that a lower amount of gp91phox and p22phox protein co-immunoprecipitated with TSPO suggesting a disruption of the TSPO-NOX2 subunits association. TSPO immuno-gold electron microscopy confirmed that TSPO is present in the outer mitochondrial membrane but it is also found in the endoplasmic reticulum (ER), mitochondria-associated ER membrane (MAM), and in the plasma membrane. TSPO localization at the MAM may represent a subcellular site where TSPO interacts with gp91phox and p22phox since the MAM is a point of communication between outer mitochondria membrane proteins (TSPO) and ER proteins (gp91phox and p22phox) where they mature and form the cytochrome b558 (Cytb558) heterodimer. We also found that an acute burst of reactive oxygen species (ROS) increased TSPO levels on the surface of microglia and this effect was abrogated by a ROS scavenger. These results suggest that ROS production may alter the subcellular distribution of TSPO. Collectively, our findings suggest that in microglia, TSPO is associated with the major NOX2 subunits gp91phox and p22phox. We hypothesize that this interaction may regulate Cytb558 formation and modulate NOX2 levels, ROS production, and redox homeostasis in microglia.
The N-acyl homoserine-lactone depleted Rhizobium radiobacter mutant RrF4NM13 shows reduced growth-promoting and resistance-inducing activities in mono- and dicotyledonous plants
Authors: Alabid Ibrahim , Hardt Martin , Imani Jafargholi , Hartmann Anton , Rothballer Michael , Li Dan , Uhl Jenny , Schmitt-Kopplin Philippe , Glaeser Stefanie , Kogel Karl-Heinz
Published: August 2020

The Alphaproteobacterium Rhizobium radiobacter (syn. Agrobacterium tumefaciens, “A. fa brum”) can live in close association with the sebacinoid fungus Serendipita (syn. Piriformospora) indica that forms a mutualistic Sebacinalean symbiosis with a wide range of host plants. The endobacterial strain R. radiobacter F4 (RrF4), which was originally isolated from the fungus, has plant growth promotion and resistance-inducing activities resembling the beneficial activities known from the endobacteria-containing S. indica. The mechanism by which free endobacterial cells influence growth and disease resistance of colonized host plants is not fully understood. Here, we show that RrF4 produces a spectrum of quorum sensing-mediating N-acyl-homoserine lactones (AHLs) with acyl chains of C8, C10, and C12 as well as hydroxyl- or oxo-substitutions at the C3 position. In addition, and in line with previous findings showing that AHLs increase plant biomass and induce systemic resistance, the AHL-depleted lactonase-overexpressing transconjugant RrF4NM13 was partially compromised in promoting growth and inducing resistance against bacterial pathogens in both Arabidopsis thaliana and wheat (Triticum aestivum). Scanning and transmission electron microscopy proved that RrF4NM13, in contrast to RrF4, does not form cellulose-like fiber scaffolds for efficient root surface attachment. Moreover, RrF4NM13 does not penetrate into the intercellular space of the cortical tissue, which in contrast is strongly colonized by RrF4. We discuss the possibility that AHLs contribute to the outcome of the Sebacinalean symbiosis.
Reputation systems and recruitment in online labor markets: insights from an agent-based model
Authors: Lukac Martin , Grow André
Published: August 2020

Online labor markets—freelance marketplaces, where digital labor is distributed via a web-based platform—commonly use reputation systems to overcome uncertainties in the hiring process, that can arise from a lack of objective information about employees’ abilities. Research shows, however, that reputation systems tend to create winner-takes-all dynamics, in which differences in candidates’ reputations become disconnected from differences in their objective abilities. In this paper, we use an empirically validated agent-based computational model to investigate the extent to which reputation systems can create segmented hiring patterns that are biased toward freelancers with good reputation. We explore how jobs and earnings become distributed on a stylized platform, under different contextual conditions of information asymmetry. Our results suggest that information asymmetry influences the extent to which reputation systems may lead to inequality between freelancers, but contrary to our expectations, lower levels of information asymmetry can facilitate higher inequality in outcomes.
Une recherche citoyenne sur l’article 12 de la convention de l’ONU sur les droits des personnes handicapées
Authors: Eyraud Benoit , Béal Arnaud , Bezghiche Nacerdine , Bonnot-Briey Stef , Bruno Chantal , Cattez Erick , Cobbaut Jean-Philippe , Daniel Sylvie , François Guillaume , Grard Julien , Klein Gael , Lalemant Michel , Lefebvre Céline , Lemard Valérie , Lequien Jacques , Letailleur Céline , Levray Claudine , Losson Marc , Marques Ana , Meile Bernard , Ordener Nicolas , Romdhani Mouna , Saenen Nicolas , Saetta Sébastien , Taran Iuliia , Vuattouxy Florie
Published: August 2020

Dans cet article, nous présentons les résultats d’un programme de recherche-action participative en France sur l’exercice des droits de l’homme et la prise de décision assistée et substitutive, inspiré de la Convention Internationale relative aux droits des personnes handicapées (“CIDPH”). Réunissant des personnes ayant le vécu du handicap, des universitaires et des professionnels de la santé et de l’aide sociale, le projet utilise la méthode de la “construction par l’expérience du problème public” pour transformer l’expérience en expertise collective. Cela a permis d’explorer le soutien dont les personnes en situation de vulnérabilité, pour lesquels la capacité à exercer les droits s’est affaiblie, ont besoin pour prendre des décisions dans leur vie quotidienne et participer de manière significative au débat public. Le lien entre la conscience/connaissance des droits et leur exercice est discuté. Nous défendons la nécessité d’équilibrer les positions des différents contributeurs dans la recherche-action participative, de manière raisonnée, en reconnaissant la participation scientifique et citoyenne de tous les acteurs.
Observing System Impact on Ionospheric Specification Over China Using EnKF Assimilation
Authors: He Jianhui , Yue Xinan , Hu Lianhuan , Wang Junyi , Li Mingyuan , Ning Baiqi , Wan Weixing , Xu Jiyao
Published: August 2020

Accurate ionospheric specification for the current and future is one of the key tasks in operational space weather. In this work, we have assessed the effect of a dense ground network consisting of different radio instruments either developed or under developing on ionosphere nowcasting and forecasting over China and adjacent region (0–60°N and 70–140°E) through observing system simulation experiments. The data assimilation system is an Ensemble Kalman filter (EnKF) ionosphere and thermosphere data assimilation algorithm. The National Center for Atmospheric Research Thermosphere Ionosphere Electrodynamics General Circulation Model is used as a background model. Effects of different observation types, including the slant total electron content from Beidou System geostationary satellite and Global Position System and electron density observations from ionosondes and incoherent scattering radar on the ionospheric nowcasting and forecasting, are examined by the accurate specification of ionosphere key parameters (total electron content and 3‐D electron density). We found that simultaneously assimilating different observation types can greatly improve the quality of ionosphere specification. Furthermore, updating the thermospheric state variables in the coupled thermosphere‐ionosphere forecast model in the assimilation step plays an important role in improving the ionosphere forecasting. The ionosphere forecasting capability can last longer (>24 hr) in each observing system simulation experiment due to the adjusted thermosphere states. This study can provide a reference for observing system design over the China region and future ionosphere forecasting operation.
Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours
Authors: Kristeleit Rebecca , Evans Jeffry , Molife L. Rhoda , Tunariu Nina , Shaw Heather , Slater Sarah , Haris Noor R. Md , Brown Nicholas F. , Forster Martin D. , Diamantis Nikolaos , Rulach Robert , Greystoke Alastair , Asghar Uzma , Rata Mihaela , Anderson Stephanie , Bachmann Felix , Hannah Alison , Kaindl Thomas , Lane Heidi A. , Larger Patrice J. , Schmitt-Hoffmann Anne , Engelhardt Marc , Tzankov Alexandar , Plummer Ruth , Lopez Juanita
Published: August 2020

Background

BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.

Methods

This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).

Results

Seventy-three patients received BAL101553 at doses of 15–80 mg/m2(phase 1,n = 24; phase 2a,n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population.

Conclusions

The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties.

Clinical trial registration

EudraCT: 2010-024237-23.
First-in-human, dose-escalation, phase 1 study of anti-angiopoietin-2 LY3127804 as monotherapy and in combination with ramucirumab in patients with advanced solid tumours
Authors: Martin-Liberal Juan , Hollebecque Antoine , Aftimos Philippe , Jungels Christiane , Martin-Romano Patricia , Rodon Jordi , Kremer Jill Dolores , Zhang Wei , Bendell Johanna
Published: August 2020

Background

This is the first-in-human study of novel anti-angiopoietin-2 (Ang-2) monoclonal antibody LY3127804 as monotherapy and in combination with ramucirumab in advanced solid tumours.

Methods

Patients received intravenous LY3127804 monotherapy (4, 8, 12, 16, 20 and 27 mg/kg) in part A; LY3127804 (8, 12, 16, 20 and 27 mg/kg) with 8 mg/kg ramucirumab in part B; and LY3127804 (20 mg/kg) with 12 mg/kg ramucirumab in part C. Treatments were administered every 2 weeks (Q2W) during 28-day cycles. Dose-escalation was based on cycle 1 dose-limiting toxicities (DLTs).

Results

Sixty-two patients were treated in part A (n = 20), part B (n = 35) and part C (n = 7). Constipation, diarrhoea and fatigue were the most common treatment-emergent adverse events (TEAEs) in part A; hypertension and peripheral oedema were the most frequent TEAE in parts B and C. No DLT was observed and maximum tolerated dose for LY3127804 was not reached. Four patients achieved partial response with combination therapy (clear cell endometrial carcinoma, cervix squamous cell carcinoma, carcinoma of unknown primary and gastroesophageal junction carcinoma), 29 achieved stable disease, and 24 had progressive disease.

Conclusions

LY3127804 monotherapy and its combination with ramucirumab are well tolerated. LY3127804 20 mg/kg was the recommended Phase 2 dose.
Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models
Authors: Dunlop Charles R. , Wallez Yann , Johnson Timothy Isaac , Bernaldo de Quirós Fernández Sandra , Durant Stephen T. , Cadogan Elaine B. , Lau Alan , Richards Frances M. , Jodrell Duncan I.
Published: August 2020

Background

Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC.

Methods

Through kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo.

Results

Complete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts.

Conclusions

ATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.
Vehicle counting and traffic flow parameter estimation for dense traffic scenes
Authors: Li Shuang , Chang Faliang , Liu Chunsheng , Li Nanjun
Published: August 2020

The vision‐based traffic flow parameter estimation is a challenging problem especially for dense traffic scenes, due to the difficulties of occlusion, small‐size and dense traffic etc. Yet, previous methods mainly use detection and tracking methods to do vehicle counting in non‐dense traffic scenes and few of them further estimate traffic flow parameters in dense traffic scenes. A framework is proposed to count vehicles and estimate traffic flow parameters in dense traffic scenes. First, a pyramid‐YOLO network is proposed for detecting vehicles in dense scenes, which can effectively detect small‐size and occluded vehicles. Second, the authors design a line of interest counting method based on restricted multi‐tracking, which counts vehicles crossing a counting line at a certain time duration. The proposed tracking method tracks short‐term vehicle trajectories near the counting line and analyses the trajectories, thus improving tracking and counting accuracy. Third, based on the detection and counting results, an estimation model is proposed to estimate traffic flow parameters of volume, speed and density. The evaluation experiments on the databases with dense traffic scenes show that the proposed framework can efficiently count vehicles and estimate traffic flow parameters with high accuracy and outperforms the representative estimation methods in comparison.
Clinical Presentation of Chronic Traumatic Encephalopathy
Authors: Mariani Megan , Alosco Michael L. , Mez Jesse , Stern Robert A.
Published: August 2020

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts (RHI), such as those received in contact/collision sports, blast injury in military veterans, and domestic violence. Currently, CTE can only be diagnosed following death. Although the clinical features of former boxers have been described for almost a century, and there is increasing evidence of long-term cognitive and neuropsychiatric impairments in living former American football players, the specific clinical presentation associated with underlying CTE neuropathology remains unclear. These features include diverse and nonspecific changes in cognition, mood, behavior, and motor functioning. Currently, there are no validated and widely accepted clinical diagnostic criteria. Proposed criteria are primarily based on retrospective telephonic interviews with the next of kin of individuals who were diagnosed with CTE postmortem. Prospective studies involving individuals presumably at high risk for CTE are underway; these will hopefully clarify the clinical features and course of CTE, allow the diagnostic criteria to be refined, and lead to the development and validation of in vivo biomarkers. This article reviews what is currently known about the clinical presentation of CTE and describes the evolution of this knowledge from early case reports of “punch drunk” boxers through larger case series of neuropathologically confirmed CTE. This article concludes with a discussion of gaps in research and future directions to address these areas.
Fluid Biomarkers for Chronic Traumatic Encephalopathy
Authors: Shahim Pashtun , Gill Jessica M. , Blennow Kaj , Zetterberg Henrik
Published: August 2020

Chronic traumatic encephalopathy (CTE) is a neuropathological condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. Currently, there is no fluid or imaging biomarker for diagnosing CTE during life. Based on retrospective clinical data, symptoms of CTE include changes in behavior, cognition, and mood, and may develop after a latency phase following the injuries. However, these symptoms are often nonspecific, making differential diagnosis based solely on clinical symptoms unreliable. Thus, objective biomarkers for CTE pathophysiology would be helpful in understanding the course of the disease as well as in the development of preventive and therapeutic measures. Herein, we review the literature regarding fluid biomarkers for repetitive concussive and subconcussive head trauma, postconcussive syndrome, as well as potential candidate biomarkers for CTE. We also discuss technical challenges with regard to the current fluid biomarkers and potential pathways to advance the most promising biomarker candidates into clinical routine.
Measuring the usability of machine translation in the classroom context
Authors: Yang Yanxia , Wang Xiangling , Yuan Qingqing
Published: August 2020

Usability is a key factor for increasing adoption of machine translation. This study aims to measure the usability
of machine translation in the classroom context by comparing translation students’ machine translation post-editing output with
their manual translation in two comparable translation tasks. Three dimensions of usability were empirically measured:
efficiency, effectiveness, and satisfaction. The findings suggest that machine translation
post-editing is more efficient than human translation and post-editing produces fewer errors than human translation. While the
types of errors vary, errors in terms of accuracy outnumber those related to fluency. In addition, participants perceive the
amount of time and work that is saved when post-editing to be greater benefit than the overall utility of post-editing. Likewise,
students report a strong desire to learn post-editing skills in training programs.
Characterization of collagenase found in the nonpathogenic bacterium Lysinibacillus sphaericus VN3
Authors: Hoa Bach Thi Mai , Pham Thanh Huyen , Dinh Truong Son , Takagi Hiroshi
Published: August 2020

High collagenolytic activity has been detected in pathogenic bacteria. Collagenase plays an essential role in the invasion step in animals and humans. In this study, we characterized collagenase found in the nonpathogenic bacterium Lysinibacillus sphaericus VN3, which was isolated from soil in Vietnam. The collagenase activity of the purified enzyme was strongly inhibited by Cu2+, but it was significantly increased by Zn2+. The purified enzyme with a molecular mass of approximately 110 kDa exhibited collagenolytic, gelatinolytic, and caseinolytic activity. The kinetic studies showed that this enzyme had greater hydrolyzing activity toward collagen and gelatin compared with casein. Based on the ratio Vmax/Km, collagen is likely to be the best substrate among three proteins. We found that this collagenase could digest small pieces of bovine skin and tendon into a collagen solution. Interestingly, at pH 6.0–8.0, the soluble collagen could form a collagen membrane, which is useful as a wound-healing biomaterial.
Nested Variant of Urothelial Carcinoma Is a Luminal Bladder Tumor With Distinct Coexpression of the Basal Marker Cytokeratin 5/6
Authors: Johnson Steven M , Khararjian Armen , Legesse Teklu B , Khani Francesca , Robinson Brian D , Epstein Jonathan I , Wobker Sara E
Published: August 2020

Objectives

The nested variant of urothelial carcinoma (NVUC) is a rare bladder tumor that may possess a luminal molecular phenotype. We sought to determine whether a small immunohistochemical (IHC) panel using common surrogates for molecular phenotypes would reliably classify a cohort of pure NVUC cases.

Methods

IHC staining with a panel composed of markers for basal subtypes (CK5/6, CK14) and luminal subtypes (FOXA1, GATA3) was performed on pure small NVUC cases (n = 23) and 5 large NVUC cases (n = 5). Scoring of IHC stains was performed semiquantitatively. Individual cases were analyzed using previously reported IHC-based surrogates for molecular subtype.

Results

The phenotype of NVUC was classified as luminal from 60.1% (FOXA1+/CK5/6−) to 100% (GATA3+/CK14−) of cases using composite phenotypes. No cases possessed a basal or squamous cell carcinoma–like phenotype. The majority of small NVUC cases (69.5%) showed subset CK5/6 expression distinctly localized to the basal layers of tumor cell nests. Intratumoral heterogeneity was also noted in CK5/6 (21.7% of small NVUC cases) but no other markers.

Conclusions

NVUC appears to express markers of both basal and luminal bladder tumors. Definitive gene expression profiling may be valuable to further characterize this unique histologic variant.
Variations in genetic structure and male genitalia suggest recent lineage diversification in the Neotropical dung beetle complexCanthon cyanellus(Scarabaeidae: Scarabaeinae)
Authors: Nolasco-Soto Janet , Favila Mario E , Espinosa De Los Monteros Alejandro , González-Astorga Jorge , Halffter Gonzalo , Valdez-Carrasco Jorge , Noriega Jorge Ari , Galante Eduardo
Published: August 2020

We analysed the genetic divergence and morphology of the aedeagus (i.e. phallobase and parameres) in Canthon cyanellus at different geographical levels. The results from both approaches were compared with the current taxonomic assignment of the C. cyanellus complex, which includes three subspecies. We found a high variation in all the morphological characters of the aedeagus in the populations analysed; the morphometric variation was not geographically structured, either by population or by region. The genealogical analysis indicates a significant genetic structure that does not match either the morphological variation in the male genitalia or the previous subspecific taxonomic classification. Our results suggest that the morphological variation of the aedeagus is seemingly not an isolating reproductive barrier and that the intra- and interpopulation morphological variability of the aedeagus in the C. cyanellus complex does not permit the division into several species. We suggest that other evolutionary forces, such as genetic drift and sexual selection, have influenced the evolution of the male genitalia and the incipient differentiation of this species complex.
Evaluation of Fontan failure by classifying the severity of Fontan-associated liver disease: a single-centre cross-sectional study
Authors: Schleiger Anastasia , Kramer Peter , Salzmann Madeleine , Danne Friederike , Schubert Stephan , Bassir Christian , Müller Tobias , Tacke Frank , Müller Hans-Peter , Berger Felix , Photiadis Joachim , Ovroutski Stanislav
Published: August 2020

OBJECTIVES

Fontan-associated liver disease (FALD) is a hallmark of the failing Fontan circulation, but no general classification of FALD severity exists. In this study, we propose a scoring system to grade the severity of FALD and analyse its applicability for evaluation of Fontan failure.

METHODS

From 2017 to 2019, a total of 129 successive Fontan patients received a comprehensive hepatic assessment. The FALD score was based on results from laboratory testing, hepatic ultrasound and transient elastography by assigning scoring points for each abnormality detected. FALD severity was graded mild, moderate and severe. Haemodynamic assessment was performed using echocardiography, cardiopulmonary exercise testing and catheterization.

RESULTS

FALD was graded absent/ mild, moderate and severe in 53, 26 and 50 patients, respectively. Cardiopulmonary capacity was significantly impaired in patients with severe FALD compared to patients with absent/mild FALD (P = 0.001). The FALD score significantly correlated with pulmonary artery pressure (P = 0.001), end-diastolic ventricular pressure (P < 0.001), hepatic venous pressure (P = 0.004) and wedged hepatic venous pressure (P = 0.009). Fontan failure was present in 21 patients. FALD was graded moderate in 2 and severe in 19 of these patients. The FALD score accurately discriminated patients with and without Fontan failure (sensitivity 90.5%, specificity 71.3%).

CONCLUSIONS

The FALD score significantly correlates with impaired Fontan haemodynamics. A cut-off value ≥6.0 has a high diagnostic accuracy in detecting Fontan failure.

Clinical trial registry

DRKS (GCTR, German clinical trial registry)

Clinical trial registration number

DRKS00015039
Adopt a Bacterium: a professional development opportunity for teacher assistants
Authors: Taschner N P , de Almeida L G , Pose R A , Ferreira R C C
Published: August 2020

Science teaching in most Brazilian Universities tends to focus mainly on lectures and provides few opportunities for the development of modern teaching skills. Our group developed an online tool called Adopt a Bacterium, which consists on a Facebook group where teacher assistants (TAs) can interact with students and have a first contact with student-focused learning approaches. This work shows the TAs’ own assessment of how the tool could be further explored to help them develop skills and become better teachers.
Searching for principles of microbial physiology
Authors: Bruggeman Frank J , Planqué Robert , Molenaar Douwe , Teusink Bas
Published: August 2020

Why do evolutionarily distinct microorganisms display similar physiological behaviours? Why are transitions from high-ATP yield to low(er)-ATP yield metabolisms so widespread across species? Why is fast growth generally accompanied with low stress tolerance? Do these regularities occur because most microbial species are subject to the same selective pressures and physicochemical constraints? If so, a broadly-applicable theory might be developed that predicts common microbiological behaviours. Microbial systems biologists have been working out the contours of this theory for the last two decades, guided by experimental data. At its foundations lie basic principles from evolutionary biology, enzyme biochemistry, metabolism, cell composition and steady-state growth. The theory makes predictions about fitness costs and benefits of protein expression, physicochemical constraints on cell growth and characteristics of optimal metabolisms that maximise growth rate. Comparisons of the theory with experimental data indicates that microorganisms often aim for maximisation of growth rate, also in the presence of stresses; they often express optimal metabolisms and metabolic proteins at optimal concentrations. This review explains the current status of the theory for microbiologists; its roots, predictions, experimental evidence and future directions.
Helmert transformation strategies in analysis of GPS position time-series
Authors: Guo Shiwei , Shi Chuang , Wei Na , Li Min , Fan Lei , Wang Cheng , Zheng Fu
Published: August 2020

Global positioning system (GPS) position time-series generated using inconsistent satellite products should be aligned to a secular Terrestrial Reference Frame by Helmert transformation. However, unmodelled non-linear variations in station positions can alias into transformation parameters. Based on 17 yr of position time-series of 112 stations produced by precise point positioning (PPP), we investigated the impact of network configuration and scale factor on long-term time-series processing. Relative to the uniform network, the uneven network can introduce a discrepancy of 0.7–1.1 mm, 21.3–27.5 μas and 1.3 mm in terms of root mean square (RMS) for the translation, rotation and scale factor (if estimated), respectively, no matter whether the scale factor is estimated. The RMS of vertical annual amplitude differences caused by such network effect reaches 0.5–0.6 mm. Whether estimating the scale factor mostly affects the Z-translation and vertical annual amplitude, leading to a difference of 1.3 mm when the uneven network is used. Meanwhile, the annual amplitude differences caused by the scale factor present different geographic location dependences over the north, east and up components. The seasonal signals derived from the transformation using the uniform network and without estimating scale factor have better consistency with surface mass loadings with more than 41 per cent of the vertical annual variations explained. Simulation studies show that 40–50 per cent of the annual signals in the scale factor can be explained by the aliasing of surface mass loadings. Another finding is that GPS draconitic errors in station positions can also alias into transformation parameters, while different transformation strategies have limited influence on identifying the draconitic errors. We suggest that the uniform network should be used and the scale factor should not be estimated in Helmert transformation. It is also suggested to perform frame alignment on PPP time-series, even though the used satellite products belong to a consistent reference frame, as the origin of PPP positions inherited from satellite orbits and clocks is not so stable during a long period. With Helmert transformation, the seasonal variations would better agree with surface mass loadings, and noise level of time-series is reduced.