bluuebunny/crossref_metadata_2025 huggingface dataset:
Innovation and innovator assessment in R&I ecosystems: the case of the EU Framework Programme
Authors: Nepelski Daniel , Van Roy Vincent
Published: June 2020

The EU Framework Programme (FP) has evolved from supporting pre-competitive research to cover the entire innovation value chain and became the world’s largest research and innovation (R&I) ecosystem. It facilitates the creation of R&I networks among organizations from around the world. To oversee and manage the innovation activities of complex collaborative R&I projects, new data, indicators and tools were needed. We present the Innovation Radar (IR), an initiative of the European Commission to identify and manage innovations and innovators in the FP R&I ecosystem. The IR is used as an intelligence platform providing insights on innovation activities in large collaborative R&I projects. The internal IR tools allow policy officers to monitor R&I projects and provide custom support to facilitate the commercialisation of their results. External actors use the public IR data platform to seek for collaborative partners or for investment opportunities.
What would it mean for natural language to be the language of thought?
Authors: Dupre Gabe
Published: June 2020

Traditional arguments against the identification of the language of thought with natural language assume a picture of natural language which is largely inconsistent with that suggested by contemporary linguistic theory. This has led certain philosophers and linguists to suggest that this identification is not as implausible as it once seemed. In this paper, I discuss the prospects for such an identification in light of these developments in linguistic theory. I raise a new challenge against the identification thesis: the existence of ungrammatical but acceptable expressions seems to require a gap between thought and language. I consider what must be the case in order for this objection to be dealt with.
Responses of a two degrees-of-freedom system with uncertain parameters in the vicinity of resonance 1:1
Authors: Awrejcewicz Jan , Cheaib Akram , Losyeva Nataliya , Puzyrov Volodymyr
Published: June 2020

We analyze the dynamics of a nonlinear mechanical system under the influence of an external harmonic force. The system consists of a linear oscillator (primary mass) and attached nonlinear dynamic absorber. It is supposed that the frequency of the external force is close to the natural frequency of the main mass. Assuming that the parameters of the system are uncertain, the stability conditions of the stationary regimes of the averaged equations are obtained analytically; these regimes correspond to the quasi-periodic motions of the original input system. An analytical approach to the problem of selecting the parameters of a dynamic absorber is proposed in order to reduce the amplitude of oscillations of the main system. The results obtained are compared with the results of the numerical integration of the equations of the motion with different initial conditions and parameter values.
Vehicle Attribute Recognition by Appearance: Computer Vision Methods for Vehicle Type, Make and Model Classification
Authors: Ni Xingyang , Huttunen Heikki
Published: June 2020

This paper studies vehicle attribute recognition by appearance. In the literature, image-based target recognition has been extensively investigated in many use cases, such as facial recognition, but less so in the field of vehicle attribute recognition. We survey a number of algorithms that identify vehicle properties ranging from coarse-grained level (vehicle type) to fine-grained level (vehicle make and model). Moreover, we discuss two alternative approaches for these tasks, including straightforward classification and a more flexible metric learning method. Furthermore, we design a simulated real-world scenario for vehicle attribute recognition and present an experimental comparison of the two approaches.
The acrid raphides in tuberous root of Pinellia ternata have lipophilic character and are specifically denatured by ginger extract
Authors: Fueki Tsukasa , Tanaka Koichiro , Obara Kunihiko , Kawahara Ryudo , Namiki Takao , Makino Toshiaki
Published: June 2020

Unprocessed dried tuberous root of Pinellia ternata (Pinellia Tuber) has been used as a component of traditional Japanese Kampo medicine, while this crude drug is usually used after processing with Ginger in traditional Chinese medicine (TCM). It is known that the raphides contained in unprocessed Pinellia Tuber can induce severe acrid irritation of the oral and laryngopharynx mucosa when it is boiled insufficiently. However, the mechanism of the inducing irritation by the raphides nor that of the detoxification by heat or processing with Ginger have been left unclear, mainly because of the difficulties in the extraction and the purification of the raphides and in the assays of acridity. In this study, we developed an easy protocol that can be used to collect raphides from unprocessed Pinellia Tuber and an assay protocol that can be used to evaluate the acridity of the raphides in vitro. The raphides of Pinellia Tuber were discovered to have a lipophilic character and to be collected easily by the extraction using petroleum ether. It was also found that the denaturation of the raphides could be assayed by the dispersity of them in petroleum ether layer of the water/petroleum ether partition, and the acridity of the raphides was found to be in correlation with the assayed denaturation. The raphides were denatured by heat, methanol, or Ginger extract and the denaturing activity of Ginger on raphides was found to be attributable to its lipophilic and thermostable components, which may explain the meaning of the processing of Pinellia Tuber with Ginger in TCM, and may lead to the development of an easier and safer protocol to administer Pinellia Tuber. In addition, it was found that rinsing the mouth with salad oil can effectively relieve irritation of the oral mucosa caused by unprocessed Pinellia Tuber, probably due to the lipophilicity of the raphides.

Graphic abstract
Prävention berufsbedingter Erkrankungen durch Lehrkräfte
Authors: Wilke Annika , Hansen Andreas , Ludewig Michaela , Rocholl Marc , John Swen Malte
Published: June 2020

Hintergrund

Aufgrund ihrer technischen Eigenschaften werden Epoxidharze (Kunstharze) in vielen Berufen eingesetzt. Wegen ihres hohen Allergiepotenzials ist ein adäquates Hautschutzverhalten bei der Verarbeitung von hoher Bedeutung. Lehrkräfte an Berufsschulen können als Multiplikator*innen fungieren, damit Auszubildende bereits beim Erlernen eines Berufs die notwendigen Kenntnisse und Fertigkeiten erwerben und Hautschutz als selbstverständlichen Teil der Arbeitsroutinen internalisieren.

Ziel der Arbeit

Das konzeptionelle Projekt „EpoxSafe@School“ zielte darauf ab, Unterrichtsmaterialien zur Prävention epoxidharzbedingter Hauterkrankungen für die Berufsschule zu entwickeln, die auf dem wissenschaftlichen Erkenntnisstand basieren und an die Bedürfnisse von Lehrkräften angepasst sind.

Material und Methoden

Im Projektverlauf wurden die Anforderungen und Bedürfnisse von Lehrkräften an durch fremde Personen erstellte Unterrichtsmaterialien im Rahmen von zwei Fokusgruppendiskussionen erhoben. Die Ergebnisse wurden bei der didaktischen Konstruktion der Materialien berücksichtigt. Ferner erfolgten Recherchen (z. B. zur Evidenz, zum Setting Berufsschule) als Grundlage für die Entwicklung der Materialien.

Ergebnisse und Diskussion

Von den Lehrkräften wurden folgende Anforderungen an fremd erstellte Materialien formuliert: methodische Variabilität, Flexibilität und Veränderbarkeit, Exemplarität, Alltagsnähe, Berufsbezug sowie die Berücksichtigung des curricularen Rahmens. Die vor diesem Hintergrund entwickelten Materialien (z. B. Schüler‑/Lehrertexte, Arbeitsblätter, Experimente) sind seit Projektende frei verfügbar. Ausblickend sind Untersuchungen zur Bewertung der Materialien durch Lehrkräfte und Auszubildende sowie zum Praxiseinsatz und deren möglicher Effekte empfehlenswert.
Histories of mathematical practice: reconstruction, genealogy, and the unruly pasts of ruly knowledge
Authors: Barany Michael J.
Published: June 2020

Histories of mathematical practice account for mathematical knowledge and action by interpreting presently-available evidence as traces of the events, contexts, and relations that make up the past. Interpretations depend on the assumptions one makes about how mathematical knowledge works, insofar as it is knowledge and insofar as it is mathematical. Though the specific rules and their meanings can differ from context to context, mathematics is a kind of ruly knowledge, expected to follow orderly patterns and principles wherever it is found. The contexts and activities of mathematical practice—how that knowledge is made, shared, applied, and understood—are necessarily less ruly, and different practices leave or occlude different kinds of evidence for historical interpretation. The apparent ruliness of mathematics can be both a resource and an obstacle for understanding its unruly pasts. Historians’ interpretive assumptions and goals have been shaped by centuries of interaction between mathematics research, history, and education.

As a guide for mathematics educators and education researchers to historical perspectives on mathematical practice, this article briefly introduces four major interpretive traditions that inform the present discipline of mathematics history. It then illustrates some interpretive approaches and challenges through the history of blackboards in mathematical practice before explaining the two broad kinds of historical interpretation applied to mathematical practices. Reconstruction involves understanding the conditions and contexts of practices in a single historical moment. Genealogy, by contrast, connects elements of the past across time through transmission, interpretation, adaptation, and other kinds of preservation and change.
Born which Way? ADHD, Situational Self-Control, and Responsibility
Authors: Koi Polaris
Published: June 2020

Debates concerning whether Attention Deficit/Hyperactivity Disorder (ADHD) mitigates responsibility often involve recourse to its genetic and neurodevelopmental etiology. For such arguments, individuals with ADHD have diminished self-control, and hence do not fully satisfy the control condition for responsibility, when there is a genetic or neurodevelopmental etiology for this diminished capacity. In this article, I argue that the role of genetic and neurobiological explanations has been overstated in evaluations of responsibility. While ADHD has genetic and neurobiological causes, rather than embrace the essentialistic notion that it directly diminishes self-control and, therefore, responsibility, we ought to think of ADHD as constraining only some self-control practices. In particular, situational self-control strategies remain feasible for people with ADHD. However, not all individuals have access to these strategies. I suggest a way to evaluate responsibility in terms of situational rather than agential pleas, which tracks whether the individual had access to self-control behaviors. While I restrict my discussion to ADHD, the access-based approach is also relevant for assessments of responsibility for other cases where self-control failures are at stake.
Der Türkise Prachtgrundkärpfling – ein Leben im Zeitraffer
Authors: Krug Johannes , Richter Annekatrin , Reuter Hanna , Englert Christoph
Published: June 2020

Nothobranchius furzeri is a killifish from southeast Africa with an extremely short lifespan. Aging of this fish shows significant similarities to the aging process in mammals including humans. N. furzeri is thus an attractive model organism for scientists in the field of aging research. Here, we present some key aspects of the biology of the killifish and discuss how this fish can help to better understand aging and aging-related diseases.
Loops und Tunnel: unterschätzte Elemente in Enzymen
Authors: Heinemann Peter M. , Rapp Lea R. , Hauer Bernhard
Published: June 2020

In enzymes, the active site is the location where substrates are chemically converted. If this site is deeply buried within the protein, substrates must pass not only through the body of the protein via a tunnel, but also flexible, site-decorating loops to access the active site. These elements can act as filters that influence on both substrate specificity and activity. Identifying and understanding how they exert such control has been of growing interest over the past several years.
Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions
Authors: Kucera Radek , Pecen Ladislav , Topolcan Ondrej , Dahal Anshu Raj , Costigliola Vincenzo , Giordano Frank A. , Golubnitschaja Olga
Published: June 2020

In the early twenty-first century, societies around the world are facing the paradoxal epidemic development of PCa as a non-communicable disease. PCa is the most frequently diagnosed cancer for men in several countries such as the USA. Permanently improving diagnostics and treatments in the PCa management causes an impressive divergence between, on one hand, permanently increasing numbers of diagnosed PCa cases and, on the other hand, stable or even slightly decreasing mortality rates. Still, aspects listed below are waiting for innovate solutions in the context of predictive approaches, targeted prevention and personalisation of medical care (PPPM / 3PM).

PCa belongs to the cancer types with the highest incidence worldwide. Corresponding economic burden is enormous. Moreover, the costs of treating PCa are currently increasing more quickly than those of any other cancer. Implementing individualised patient profiles and adapted treatment algorithms would make currently too heterogeneous landscape of PCa treatment costs more transparent providing clear “road map” for the cost saving.

PCa is a systemic multi-factorial disease. Consequently, predictive diagnostics by liquid biopsy analysis is instrumental for the disease prediction, targeted prevention and curative treatments at early stages.

The incidence of metastasising PCa is rapidly increasing particularly in younger populations. Exemplified by trends observed in the USA, prognosis is that the annual burden will increase by over 40% in 2025. To this end, one of the evident deficits is the reactive character of medical services currently provided to populations. Innovative screening programmes might be useful to identify persons in suboptimal health conditions before the clinical onset of metastasising PCa. Strong predisposition to systemic hypoxic conditions and ischemic lesions (e.g. characteristic for individuals with Flammer syndrome phenotype) and low-grade inflammation might be indicative for specific phenotyping and genotyping in metastasising PCa screening and disease management. Predictive liquid biopsy tests for CTC enumeration and their molecular characterisation are considered to be useful for secondary prevention of metastatic disease in PCa patients.

Particular rapidly increasing PCa incidence rates are characteristic for adolescents and young adults aged 15–40 years. Patients with early onset prostate cancer pose unique challenges; multi-factorial risks for these trends are proposed. Consequently, multi-level diagnostics including phenotyping and multi-omics are considered to be the most appropriate tool for the risk assessment, prediction and prognosis. Accumulating evidence suggests that early onset prostate cancer is a distinct phenotype from both aetiological and clinical perspectives deserving particular attention from view point of 3P medical approaches.
Quantum state discrimination via repeated measurements and the rule of three
Authors: Bullock Tom , Heinosaari Teiko
Published: June 2020

The task of state discrimination for a set of mutually orthogonal pure states is trivial if one has access to the corresponding sharp (projection-valued) measurement, but what if we are restricted to an unsharp measurement? Given that any realistic measurement device will be subject to some noise, such a problem is worth considering. In this paper, we consider minimum error state discrimination for mutually orthogonal states with a noisy measurement. We show that by considering repetitions of commutative Lüders measurements on the same system we are able to increase the probability of successfully distinguishing states. In the case of binary Lüders measurements, we provide a full characterisation of the success probabilities for any number of repetitions. This leads us to identify a ‘rule of three’, where no change in probability is obtained from a second measurement but there is noticeable improvement after a third. We also provide partial results for N-valued commutative measurements where the rule of three remains, but the general pattern present in binary measurements is no longer satisfied.
An Interactive Network for End-to-End Review Helpfulness Modeling
Authors: Du Jiahua , Zheng Liping , He Jiantao , Rong Jia , Wang Hua , Zhang Yanchun
Published: June 2020

Review helpfulness prediction aims to prioritize online reviews by quality. Existing methods largely combine review texts and star ratings for helpfulness prediction. However, star ratings are used in a way that has either little representation capacity or limited interaction with review texts. As a result, rating information has yet to be fully exploited during the combination. This paper aims to overcome the two drawbacks. A deep interactive architecture is proposed to learn the text–rating interaction (TRI) for helpfulness modeling. TRI enlarges the representation capacity of star ratings while enhancing the influence of rating information on review texts. TRI is evaluated on six real-world domains of the Amazon 5-Core dataset. Extensive experiments demonstrate that TRI can better predict review helpfulness and beat the state of the art. Ablation studies and qualitative analysis are provided to further understand model behaviors and the learned parameters.
Dynamische Preisgestaltung in der digitalisierten Welt
Authors: Spann Martin , Skiera Bernd
Published: June 2020

Digitale Technologien begünstigen den Einsatz einer dynamischen Preisgestaltung, also von Preisen, die für ein prinzipiell gleiches Produkt unangekündigt variieren. Dabei werden in der öffentlichen Diskussion unterschiedliche Ausgestaltungsformen dynamischer Preise oftmals vermischt, was eine sinnvolle Analyse der Vor- und Nachteile der dynamischen Preisgestaltung erschwert. Das Ziel des Beitrags ist die Darstellung der ökonomischen Grundlagen und die Diskussion sowie Klassifikation der Ausgestaltungsmöglichkeiten der dynamischen Preisgestaltung. Darüber hinaus erfolgt eine Bewertung der Vor- und Nachteile der dynamischen Preisgestaltung aus Käufer- und Verkäufersicht. Abschließend werden Implikationen für die betriebswirtschaftliche Forschung diskutiert.
Adiponectin Reduces Embryonic Loss Rate and Ameliorates Trophoblast Apoptosis in Early Pregnancy of Mice with Polycystic Ovary Syndrome by Affecting the AMPK/PI3K/Akt/FoxO3a Signaling Pathway
Authors: Zhang Wenqian , Zuo Meng , Lu Juan , Wang Yuxia
Published: June 2020

Reports in recent years have suggested that adiponectin (APN) improves insulin resistance and inhibits apoptosis by activating the AMP-activated protein kinase (AMPK) pathway and the PI3K/Akt signaling pathway after binding to its receptor. This study aims to explore the mechanism by which APN reduces embryo loss rate and trophoblast apoptosis in early pregnancy of mice with polycystic ovary syndrome (PCOS). PCOS mice were subcutaneously injected with APN (10 μg mg kg−1 day−1) on 11 consecutive days from the 3rd day of pregnancy onwards to observe the change of the embryo loss rate of PCOS mice induced by APN. Quantitative real-time PCR and Western blot were used to determine the relative expressions of mRNA and the proteins AMPK, PI3K, and Akt in mouse uterine tissue. At the same time, primary cultured mouse villous trophoblast cells were used to further explore the underlying mechanisms in vitro. APN significantly reduces the pregnancy loss rate of PCOS mice. At the same time, APN increases phosphorylation and mRNA expression levels of AMPK, PI3K, and Akt in PCOS mouse uterine tissue. In addition, trophoblast cells of model mice were treated with APN and inhibitors, and APN was found to reduce trophoblast cell apoptosis by affecting the phosphorylation levels of AMPK, PI3K, Akt, and FoxO3a proteins. APN reduces the embryo loss rate and ameliorates trophoblast apoptosis in PCOS mice by affecting the AMPK/PI3K/AKT/FoxO3a signaling pathway.
“The internet is not private”: The role of social media in sexual health among youth in foster care
Authors: Kachingwe Olivia N. , Salerno John P. , Boekeloo Bradley O. , Fish Jessica N. , Geddings‐Hayes Melanie , Aden Faduma , Aparicio Elizabeth M.
Published: June 2020

Highlights

Foster youth use social media to establish and maintain intimate relationships.

Trust plays an integral role in how foster youth interact with others online.

Social media use can result in intimate partner violence and breached privacy.

Foster youth take concrete steps to protect themselves while online.

Parents and staff need further training on how best to support foster youth online.
Intraoperative Use of Betadine Irrigation is Associated With a 9-Fold Increased Likelihood of Penile Prosthesis Infection: Results From a Retrospective Case-Control Study
Authors: Manka Madeleine G. , Yang David , Andrews Jack , Chalmers Brian , Hebert Kevin , Köhler Tobias S. , Trost Landon
Published: June 2020

Introduction

Infection remains a persistent complication of penile prosthesis (PP) surgery. Despite popularity of Mulcahy’s PP washout protocol, Betadine has known tissue toxicity.

Aim

We evaluated PP infection rate based on the type of intraoperative irrigation used, ½ strength Betadine vs vancomycin/gentamicin.

Methods

We reviewed a prospective database of men undergoing primary, revision, and salvage PPs. No other changes to operative or perioperative techniques occurred after the change in irrigation solution. Univariate and logistic regression analyses were used to evaluate differences in infection rate with use of Betadine vs vancomycin/gentamicin irrigation. Potential confounders were reviewed.

Main Outcome Measure

The primary outcome was rate of PP infection before and after change of intraoperative irrigation.

Results

From 2014 to 2018, 217 patients underwent PP placement at our institution by a single surgeon; of whom, 21 (9.7%) experienced an infection (primary = 10 [7.1%], revision = 11 [17.19%], salvage = 0 [0%]). Overall, 152 (70%) received irrigation with Betadine and 65 (30%) with Vancomycin/Gentamicin. Univariate analysis demonstrated significantly increased infection rates with Betadine irrigation (odds ratio [OR]: 4.64, P = .006) and with revision surgery (OR: 2.68, P = .02). Significance of increased infection rate with Betadine was maintained (OR: 9.3; P = .025) after controlling for age, body mass index, Charlson comorbidity index, smoking, diabetes, primary vs revision/salvage, prior penile surgery, use of ectopic reservoir, and adjunctive glanulopexy.

Conclusions

Changing from intraoperative Betadine to vancomycin/gentamicin solution dramatically reduced infection rates among men undergoing PP placement in both primary and revision cases. We hypothesize that differences in infection rate may relate to the relative toxicity or non-sterile nature of Betadine.

Manka MG, Yang D, Andrews J, et al. Intraoperative Use of Betadine Irrigation is Associated With a 9-Fold Increased Likelihood of Penile Prosthesis Infection: Results From a Retrospective Case-Control Study. Sex Med 2020;8:422–427.
Evidence based guideline on use of ketofol (Ketamine and Propofol admixture) for procedural sedation and analgesia (PSA) in pediatrics surgery : Review article
Authors: Ali Siraj Ahmed , Aweke Zemedu , Jemal Bedru
Published: June 2020

ABSTRACT

Procedural sedation and analgesia (PSA) implies the state of drug induced tolerance of uncomfortable or painful diagnostic, interventional medical and surgical procedures. Ketofol (ketamine and Propofol mixture) is a good combination of drugs for PSA in painful procedures in pediatrics resulting in hemodynamic and respiratory safety. A combination of these drugs provides sedation, analgesia, and rapid recovery with hemodynamic stability and minimal respiratory depression. The objective of sedation during such procedures is to reduce the discomfort of the patient and to facilitate the performance of the procedure.

This systematic review was conducted according to the preferred reporting items for systematic review and meta-analysis protocol (PRISMA). Evidences for this guideline development were searched from PubMed, Google Scholar, Google search, and Medline databases with keywords.

During the review of searched literature for the guideline, important concerns discussed were patient selection and assessment (indication for PSA), monitoring of children including depth of sedation, medication administration (a combination of the agents), and criteria for postoperative discharge.

Generally, in the presence of adequate resuscitation equipment and monitoring ketamine and Propofol mixture can be used in the proportion of 1:1, 1:2, 1:3, and 1:4 safely with good respiratory and hemodynamic stability.

Highlights:
Evolution of the Asian Monsoon
Authors: Clift Peter , Holbourn Ann , France-Lanord Christian , Zheng Hongbo
Published: June 2020

Climate and topography change the characteristics of the Asian monsoon over millions of years. These changes affect the region’s climate and topography, and the cycle continues.
Tectonic Inheritance With Dipping Faults and Deformation Fabric in the Brittle and Ductile Southern California Crust
Authors: Schulte‐Pelkum Vera , Ross Zachary E. , Mueller Karl , Ben‐Zion Yehuda
Published: June 2020

Plate motions in Southern California have undergone a transition from compressional and extensional regimes to a dominantly strike‐slip regime in the Miocene. Strike‐slip motion is most easily accommodated on vertical faults, and major transform fault strands in the region are typically mapped as near vertical on the surface. However, some previous work suggests that these faults have a dipping geometry at depth. We analyze receiver function arrivals that vary harmonically with back azimuth at all available broadband stations in the region. The results show a dominant signal from contrasts in dipping foliation as well as dipping isotropic velocity contrasts from all crustal depths, including from the ductile middle to lower crust. We interpret these receiver function observations as a dipping fault‐parallel structural fabric that is pervasive throughout the region. The strike of these structures and fabrics is parallel to that of nearby fault surface traces. We also plot microseismicity on depth profiles perpendicular to major strike‐slip faults and find consistently NE dipping features in seismicity changing from near vertical (80–85°) on the Elsinore Fault in the Peninsular Ranges to 60–65° slightly further inland on the San Jacinto Fault to 50–55° on the San Andreas Fault. Taken together, the dipping features in seismicity and in rock fabric suggest that preexisting fabrics and faults may have acted as strain guides in the modern slip regime, with reactivation and growth of strike‐slip faults along northeast dipping fabrics both above and below the brittle‐ductile transition.
SUMO and cellular adaptive mechanisms
Authors: Ryu Hong-Yeoul , Ahn Seong Hoon , Hochstrasser Mark
Published: June 2020

The ubiquitin family member SUMO is a covalent regulator of proteins that functions in response to various stresses, and defects in SUMO-protein conjugation or deconjugation have been implicated in multiple diseases. The loss of the Ulp2 SUMO protease, which reverses SUMO-protein modifications, in the model eukaryote Saccharomyces cerevisiae is severely detrimental to cell fitness and has emerged as a useful model for studying how cells adapt to SUMO system dysfunction. Both short-term and long-term adaptive mechanisms are triggered depending on the length of time cells spend without this SUMO chain-cleaving enzyme. Such short-term adaptations include a highly specific multichromosome aneuploidy and large changes in ribosomal gene transcription. While aneuploid ulp2Δ cells survive, they suffer severe defects in growth and stress resistance. Over many generations, euploidy is restored, transcriptional programs are adjusted, and specific genetic changes that compensate for the loss of the SUMO protease are observed. These long-term adapted cells grow at normal rates with no detectable defects in stress resistance. In this review, we examine the connections between SUMO and cellular adaptive mechanisms more broadly.
Repurposing anthelmintic agents to eradicate resistant leukemia
Authors: Mezzatesta Caterina , Abduli Liridon , Guinot Anna , Eckert Cornelia , Schewe Denis , Zaliova Marketa , Vinti Luciana , Marovca Blerim , Tsai Yi-Chien , Jenni Silvia , Aguade-Gorgorio Julia , von Stackelberg Arend , Schrappe Martin , Locatelli Franco , Stanulla Martin , Cario Gunnar , Bourquin Jean-Pierre , Bornhauser Beat C.
Published: June 2020

Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status
Authors: Baysal Hasan , De Pauw Ines , Zaryouh Hannah , De Waele Jorrit , Peeters Marc , Pauwels Patrick , Vermorken Jan Baptist , Smits Evelien , Lardon Filip , Jacobs Julie , Wouters An
Published: June 2020

Background

The epidermal growth factor receptor (EGFR) is overexpressed by 80–90% of squamous cell carcinoma of head and neck (HNSCC). In addition to inhibiting EGFR signal transduction, cetuximab, a monoclonal antibody targeting EGFR can also bind to fragment crystallisable domain of immunoglobulins G1 present on natural killer (NK), causing antibody-dependent cellular cytotoxicity (ADCC). However, presence of cetuximab resistance limits effective clinical management of HNSCC.

Methods

In this study, differences in induction of ADCC were investigated in a panel of ten HNSCC cell lines. Tumour cells were co-cultured with NK cells and monitored using the xCELLigence RTCA.

Results

While ADCC was not influenced by HPV status, hypoxia and cetuximab resistance did affect ADCC differentially. Intrinsic cetuximab-resistant cell lines showed an increased ADCC induction, whereas exposure to hypoxia reduced ADCC. Baseline EGFR expression was not correlated with ADCC. In contrast, EGFR internalisation following cetuximab treatment was positively correlated with ADCC.

Conclusion

These findings support the possibility that resistance against cetuximab can be overcome by NK cell-based immune reactions. As such, it provides an incentive to combine cetuximab with immunotherapeutic approaches, thereby possibly enhancing the anti-tumoural immune responses and achieving greater clinical effectiveness of EGFR-targeting agents.
Twelve-year clinical trajectories of multimorbidity in a population of older adults
Authors: Vetrano Davide L. , Roso-Llorach Albert , Fernández Sergio , Guisado-Clavero Marina , Violán Concepción , Onder Graziano , Fratiglioni Laura , Calderón-Larrañaga Amaia , Marengoni Alessandra
Published: June 2020

Multimorbidity—the co-occurrence of multiple diseases—is associated to poor prognosis, but the scarce knowledge of its development over time hampers the effectiveness of clinical interventions. Here we identify multimorbidity clusters, trace their evolution in older adults, and detect the clinical trajectories and mortality of single individuals as they move among clusters over 12 years. By means of a fuzzy c-means cluster algorithm, we group 2931 people ≥60 years in five clinically meaningful multimorbidity clusters (52%). The remaining 48% are part of an unspecific cluster (i.e. none of the diseases are overrepresented), which greatly fuels other clusters at follow-ups. Clusters contribute differentially to the longitudinal development of other clusters and to mortality. We report that multimorbidity clusters and their trajectories may help identifying homogeneous groups of people with similar needs and prognosis, and assisting clinicians and health care systems in the personalization of clinical interventions and preventive strategies.
Kinetics of motile solitons in nematic liquid crystals
Authors: Aya Satoshi , Araoka Fumito
Published: June 2020

The generation of spatially localized, soliton-like hydrodynamic disturbances in microscale fluidic systems is an intriguing challenge. Herein, we introduce nonequilibrium solitons in nematic liquid crystals stimulated by an electric field. These dynamic solitons are robust as long as the electric field is maintained. Interestingly, their kinetic behaviours depend on the field condition—Tuning of the amplitude and frequency of the applied electric field alters the solitons to self-assemble into lattice ordering like physical particles or to command them to various dynamic states. Our key property to the realisation is the electrohydrodynamic instability due to the coupling between the fluid elasticity and the background convection. This paper describes a new mechanism for realising dynamic solitons in fluid systems on the basis of the electrohydrodynamic phenomena.
Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex
Authors: Watanabe Hidenori , Sano Hiromi , Chiken Satomi , Kobayashi Kenta , Fukata Yuko , Fukata Masaki , Mushiake Hajime , Nambu Atsushi
Published: June 2020

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 is strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induces prominent cortical activity: Even single-pulse, short-duration oICMS evokes long-lasting repetitive firings of cortical neurons. In addition, oICMS elicits distinct forelimb movements and muscle activity, which are comparable to those elicited by conventional electrical ICMS. The present study removes obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.
NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation
Authors: Miao Kai , Lei Josh Haipeng , Valecha Monica Vishnu , Zhang Aiping , Xu Jun , Wang Lijian , Lyu Xueying , Chen Si , Miao Zhengqiang , Zhang Xin , Su Sek Man , Shao Fangyuan , Rajendran Barani Kumar , Bao Jiaolin , Zeng Jianming , Sun Heng , Chen Ping , Tan Kaeling , Chen Qiang , Wong Koon Ho , Xu Xiaoling , Deng Chu-Xia
Published: June 2020

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.
Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons
Authors: Silva M. Catarina , Nandi Ghata A. , Tentarelli Sharon , Gurrell Ian K. , Jamier Tanguy , Lucente Diane , Dickerson Bradford C. , Brown Dean G. , Brandon Nicholas J. , Haggarty Stephen J.
Published: June 2020

Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.
Coastal sedimentation across North America doubled in the 20th century despite river dams
Authors: Rodriguez A. B. , McKee B. A. , Miller C. B. , Bost M. C. , Atencio A. N.
Published: June 2020

The proliferation of dams since 1950 promoted sediment deposition in reservoirs, which is thought to be starving the coast of sediment and decreasing the resilience of communities to storms and sea-level rise. Diminished river loads measured upstream from the coast, however, should not be assumed to propagate seaward. Here, we show that century-long records of sediment mass accumulation rates (g cm−2 yr−1) and sediment accumulation rates (cm yr−1) more than doubled after 1950 in coastal depocenters around North America. Sediment sources downstream of dams compensate for the river-sediment lost to impoundments. Sediment is accumulating in coastal depocenters at a rate that matches or exceeds relative sea-level rise, apart from rapidly subsiding Texas and Louisiana where water depths are increasing and intertidal areas are disappearing. Assuming no feedbacks, accelerating global sea-level rise will eventually surpass current sediment accumulation rates, underscoring the need for including coastal-sediment management in habitat-restoration projects.
Structure and catalytic regulation of Plasmodium falciparum IMP specific nucleotidase
Authors: Carrique Loïc , Ballut Lionel , Shukla Arpit , Varma Neelakshi , Ravi Resmi , Violot Sébastien , Srinivasan Bharath , Ganeshappa Umesh Tippagondanahalli , Kulkarni Sonia , Balaram Hemalatha , Aghajari Nushin
Published: June 2020

Plasmodium falciparum (Pf) relies solely on the salvage pathway for its purine nucleotide requirements, making this pathway indispensable to the parasite. Purine nucleotide levels are regulated by anabolic processes and by nucleotidases that hydrolyse these metabolites into nucleosides. Certain apicomplexan parasites, including Pf, have an IMP-specific-nucleotidase 1 (ISN1). Here we show, by comprehensive substrate screening, that PfISN1 catalyzes the dephosphorylation of inosine monophosphate (IMP) and is allosterically activated by ATP. Crystal structures of tetrameric PfISN1 reveal complex rearrangements of domain organization tightly associated with catalysis. Immunofluorescence microscopy and expression of GFP-fused protein indicate cytosolic localization of PfISN1 and expression in asexual and gametocyte stages of the parasite. With earlier evidence on isn1 upregulation in female gametocytes, the structures reported in this study may contribute to initiate the design for possible transmission-blocking agents.
Protein arginine deiminase 4 antagonizes methylglyoxal-induced histone glycation
Authors: Zheng Qingfei , Osunsade Adewola , David Yael
Published: June 2020

Protein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of the core histones H3 and H4. While the precise epigenetic function of this modification has not been resolved, it has been shown to associate with general chromatin decompaction and compete with arginine methylation. Recently, we found that histones are subjected to methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change chromatin architecture and the epigenetic landscape by competing with enzymatic modifications, as well as changing the overall biophysical properties of the fiber. Here, we report that PAD4 antagonizes histone MGO-glycation by protecting the reactive arginine sites, as well as by converting already-glycated arginine residues into citrulline. Moreover, we show that similar to the deglycase DJ-1, PAD4 is overexpressed and histone citrullination is upregulated in breast cancer tumors, suggesting an additional mechanistic link to PAD4’s oncogenic properties.
Toward nanoscale molecular mass spectrometry imaging via physically constrained machine learning on co-registered multimodal data
Authors: Borodinov Nikolay , Lorenz Matthias , King Steven T. , Ievlev Anton V. , Ovchinnikova Olga S.
Published: June 2020

Mass spectrometry imaging (MSI) plays a pivotal role in investigating the chemical nature of complex systems that underly our understanding in biology and medicine. Multiple fields of life science such as proteomics, lipidomics and metabolomics benefit from the ability to simultaneously identify molecules and pinpoint their distribution across a sample. However, achieving the necessary submicron spatial resolution to distinguish chemical differences between individual cells and generating intact molecular spectra is still a challenge with any single imaging approach. Here, we developed an approach that combines two MSI techniques, matrix-assisted laser desorption/ionization (MALDI) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), one with low spatial resolution but intact molecular spectra and the other with nanometer spatial resolution but fragmented molecular signatures, to predict molecular MSI spectra with submicron spatial resolution. The known relationships between the two MSI channels of information are enforced via a physically constrained machine-learning approach and directly incorporated in the data processing. We demonstrate the robustness of this method by generating intact molecular MALDI-type spectra and chemical maps at ToF-SIMS resolution when imaging mouse brain thin tissue sections. This approach can be readily adopted for other types of bioimaging where physical relationships between methods have to be considered to boost the confidence in the reconstruction product.
Two-dimensional hard-core Bose–Hubbard model with superconducting qubits
Authors: Yanay Yariv , Braumüller Jochen , Gustavsson Simon , Oliver William D. , Tahan Charles
Published: June 2020

The pursuit of superconducting-based quantum computers has advanced the fabrication of and experimentation with custom lattices of qubits and resonators. Here, we describe a roadmap to use present experimental capabilities to simulate an interacting many-body system of bosons and measure quantities that are exponentially difficult to calculate numerically. We focus on the two-dimensional hard-core Bose–Hubbard model implemented as an array of floating transmon qubits. We describe a control scheme for such a lattice that can perform individual qubit readout and show how the scheme enables the preparation of a highly excited many-body state, in contrast with atomic implementations restricted to the ground state or thermal equilibrium. We discuss what observables could be accessed and how they could be used to better understand the properties of many-body systems, including the observation of the transition of eigenstate entanglement entropy scaling from area-law behavior to volume-law behavior.
Resistance of Fritillaria imperialis to freezing stress through gene expression, osmotic adjustment and antioxidants
Authors: Hajihashemi Shokoofeh , Brestic Marian , Landi Marco , Skalicky Milan
Published: June 2020

Plant survival in response to freezing stress depends on the efficient activation of tolerance mechanisms.Fritillaria imperialisexposure to freezing stress enhanced signalling molecules Ca2+and H2O2along with overexpression of Ca2+signalling proteins (Ca2+dependent protein kinases, CPK), followed by upregulation ofNHX1(Na+/H+antiporter),LEA(late embryogenesis abundant proteins) andP5CS(1-pyrroline-5-carboxylate synthetase). Overexpression ofOsCNGC6was responsible for high accumulation Ca2+, Na+and K+. The NHX1 gene product transported Na+to vacuoles and increased cytosolic K+content to re-establish ionic homeostasis under stress conditions. The reduced water potential of leaves was due to high accumulation of osmolytes and ions. No changes were observed in relative water content of leaves, which might be correlated with overexpression of theLEAgene, which protects against dehydration. High accumulation of H2O2under freezing stress was responsible for activation of antioxidant systems involving SOD, phenols, anthocyanins, catalase and ascorbate peroxidase. Photosynthesis, suppressed in freezing-stressed plants, returned to normal levels after termination of freezing stress. Taken together, our findings suggest that Fritillaria efficiently tolerated freezing stress through induction of signalling mechanisms and overexpression of cold stress-responsive genes, and prevention of cold-induced water stress, oxidative stress and photosynthetic damage.