bluuebunny/crossref_metadata_2025 huggingface dataset:
Flexible timing of annual movements across consistently used sites by Marbled Godwits breeding in Alaska
Authors: Ruthrauff Daniel R , Tibbitts T Lee , Gill Robert E
Published: June 2019

The study of avian movement has detailed a spectrum of strategies for the timing and use of sites throughout the annual cycle, from near randomness to complete consistency. New tracking devices now permit the repeated tracking of individual animals throughout the annual cycle, detailing previously unappreciated levels of variation within migratory systems. Godwits (genus Limosa) have featured prominently in studies of avian migration, but information derived from repeated tracking of individuals is limited. The Marbled Godwit subspecies Limosa fedoa beringiae breeds on the central Alaska Peninsula, and little is known about basic aspects of its migration ecology, including the repeatability with which this population times its annual migratory movements or uses migratory and nonbreeding sites. To address these questions, we equipped 9 Marbled Godwits breeding at a site near Ugashik, Alaska, with solar-powered satellite transmitters. We tracked individuals from July, 2008 to October, 2015 and obtained repeat migratory tracks from 5 of these birds. Individuals exhibited high fidelity to breeding, nonbreeding, and migratory stopover sites across years, but in contrast to congeners that conduct consistently timed, long, nonstop migrations, beringiae Marbled Godwits exhibited low levels of individual- or population-level repeatability in the timing of migratory movements. Their relatively short migrations may enable the integration of local environmental cues, potentially facilitating individual flexibility in the timing of annual migratory movements. Curiously, if local cues ultimately drive the timing of Marbled Godwit migratory movements, the population’s relatively constrained distribution during both the breeding and nonbreeding season should serve to synchronize birds if they are responding to similar cues. That our sample of Marbled Godwits nonetheless exhibited within- and between-year variation in the timing of their migratory movements suggests a complex integration of annually variable internal and external cues.
Evaluating the taxonomic status of the Great White Heron (Ardea herodias occidentalis) using morphological, behavioral and genetic evidence
Authors: McGuire Heather L , Taylor Sabrina S , Sheldon Frederick H
Published: June 2019

The Great White Heron (GWH) has an all-white plumage and occurs in the Gulf of Mexico and Caribbean. Described originally as Ardea occidentalis, it is now considered a subspecies of Great Blue Heron (GBH; A. herodias). GWH and GBH meet in Florida Bay at the southern tip of Florida, providing the opportunity to evaluate their interaction and species status. To this end, we examined size variation and mate choice across their contact zone and genetic variation range-wide. Measurements of 7 morphological characters indicate trends, but not a significant difference, in size between GBH and GWH in southern Florida. GBH and GWH nest mainly in different places (mainland vs. islands) and at different peak times. In Florida Bay, mixed pairs occur, but white-white and blue-blue pairs are more common than in a randomly mating population. Assessing mating, however, is complicated because most, if not all, nesting blue birds are of mixed parentage. Microsatellite DNA analysis indicates that white and blue herons in Florida Bay and the outer Keys (outside Florida Bay) form a group distinct from blue forms on Florida Peninsula and elsewhere in North America. However, some gene flow occurs from white herons on the outer Keys to white and blue herons in Florida Bay, and from blue herons in Florida Bay to GBH on the Florida Peninsula. GWH alleles occur in all North American populations, but whether this is from gene flow or incomplete lineage sorting is unknown. Deciding GWH's species status is difficult. GWH and GBH meet in an ecotone where some gene flow occurs, but behavior and habitat largely isolate them. We argue in favor of splitting GWH from GBH. Regardless of how it is ultimately classified, the GWH's small population needs to be actively managed as an isolate in an extremely vulnerable environment.
Protein functional annotation of simultaneously improved stability, accuracy and false discovery rate achieved by a sequence-based deep learning
Authors: Hong Jiajun , Luo Yongchao , Zhang Yang , Ying Junbiao , Xue Weiwei , Xie Tian , Tao Lin , Zhu Feng
Published: June 2019

Functional annotation of protein sequence with high accuracy has become one of the most important issues in modern biomedical studies, and computational approaches of significantly accelerated analysis process and enhanced accuracy are greatly desired. Although a variety of methods have been developed to elevate protein annotation accuracy, their ability in controlling false annotation rates remains either limited or not systematically evaluated. In this study, a protein encoding strategy, together with a deep learning algorithm, was proposed to control the false discovery rate in protein function annotation, and its performances were systematically compared with that of the traditional similarity-based and de novo approaches. Based on a comprehensive assessment from multiple perspectives, the proposed strategy and algorithm were found to perform better in both prediction stability and annotation accuracy compared with other de novo methods. Moreover, an in-depth assessment revealed that it possessed an improved capacity of controlling the false discovery rate compared with traditional methods. All in all, this study not only provided a comprehensive analysis on the performances of the newly proposed strategy but also provided a tool for the researcher in the fields of protein function annotation.
Positive multistate protein design
Authors: Vucinic Jelena , Simoncini David , Ruffini Manon , Barbe Sophie , Schiex Thomas
Published: June 2019

Motivation

Structure-based computational protein design (CPD) plays a critical role in advancing the field of protein engineering. Using an all-atom energy function, CPD tries to identify amino acid sequences that fold into a target structure and ultimately perform a desired function. The usual approach considers a single rigid backbone as a target, which ignores backbone flexibility. Multistate design (MSD) allows instead to consider several backbone states simultaneously, defining challenging computational problems.

Results

We introduce efficient reductions of positive MSD problems to Cost Function Networks with two different fitness definitions and implement them in the Pompd (Positive Multistate Protein design) software. Pompd is able to identify guaranteed optimal sequences of positive multistate full protein redesign problems and exhaustively enumerate suboptimal sequences close to the MSD optimum. Applied to nuclear magnetic resonance and back-rubbed X-ray structures, we observe that the average energy fitness provides the best sequence recovery. Our method outperforms state-of-the-art guaranteed computational design approaches by orders of magnitudes and can solve MSD problems with sizes previously unreachable with guaranteed algorithms.

Availability and implementation

https://forgemia.inra.fr/thomas.schiex/pompd as documented Open Source.

Supplementary information

Supplementary data are available at Bioinformatics online.
Ovarian cancer and the evolution of subtype classifications using transcriptional profiling†
Authors: Cook David P , Vanderhyden Barbara C
Published: June 2019

Ovarian cancer is a complex disease with multiple subtypes, each having distinct histopathologies and variable responses to treatment. This review highlights the technological milestones and the studies that have applied them to change our definitions of ovarian cancer. Over the past 50 years, technologies such as microarrays and next-generation sequencing have led to the discovery of molecular alterations that define each of the ovarian cancer subtypes and has enabled further subclassification of the most common subtype, high-grade serous ovarian cancer (HGSOC). Improvements in mutational profiling have provided valuable insight, such as the ubiquity of TP53 mutations in HGSOC tumors. However, the information derived from these technological advances has also revealed the immense heterogeneity of this disease, from variation between patients to compositional differences within single masses. In looking forward, the emerging technologies for single-cell and spatially resolved transcriptomics will allow us to better understand the cellular composition and structure of tumors and how these contribute to the molecular subtypes. Attempts to incorporate the complexities ovarian cancer has resulted in increasing sophistication of model systems, and the increased precision in molecular profiling of ovarian cancers has already led to the introduction of inhibitors of poly (ADP-ribose) polymerases as a new class of treatments for ovarian cancer with DNA repair deficiencies. Future endeavors to define increasingly accurate classification strategies for ovarian cancer subtypes will allow for confident prediction of disease progression and provide important insight into potentially targetable molecular mechanisms specific to each subtype.
Testicular endothelial cells promote self-renewal of spermatogonial stem cells in rats†
Authors: Kim Yong-Hee , Oh Myeong-Geun , Bhang Dong Ha , Kim Bang-Jin , Jung Sang-Eun , Kim Seok-Man , Dohr Gottfried , Kim Sun-Uk , Ryeom Sandra , Ryu Buom-Yong
Published: June 2019

Spermatogonial stem cells (SSCs) are the basis of spermatogenesis in male due to their capability to multiply in numbers by self-renewal and subsequent meiotic processes. However, as SSCs are present in a very small proportion in the testis, in vitro proliferation of undifferentiated SSCs will facilitate the study of germ cell biology. In this study, we investigated the effectiveness of various cell lines as a feeder layer for rat SSCs. Germ cells enriched for SSCs were cultured on feeder layers including SIM mouse embryo-derived thioguanine and ouabain-resistant cells, C166 cells, and mouse and rat testicular endothelial cells (TECs) and their stem cell potential for generating donor-derived colonies and offspring was assessed by transplantation into recipient testes. Rat germ cells cultured on TECs showed increased mRNA and protein levels of undifferentiated spermatogonial markers. Rat SSCs derived from these germ cells underwent spermatogenesis and generated offspring when transplanted into recipients. Collectively, TECs can serve as an effective feeder layer that enhances the proliferative and self-renewal capacity of cultured rat SSCs while preserving their stemness properties.
Learning for Transdisciplinary Leadership: Why Skilled Scholars Coming Together Is Not Enough
Authors: Barrett M J , Alphonsus Khrisha B , Harmin Matt , Epp Tasha , Hoessler Carolyn , McIntyre Danielle , Reeder Bruce , Singh Baljit
Published: June 2019

Transdisciplinary research is an emerging new normal for many scientists in applied research fields, including One Health, planetary health, and sustainability. However, simply bringing highly skilled students (and faculty members) together to generate real-world solutions and policy recommendations for complex problems often fails to consistently create the desired results in transdisciplinary settings. Our research goal was to improve understanding and applications of transdisciplinary learning processes within a One Health graduate education program. This qualitative study analyzes 5 years of action research data, identifying four transdisciplinary leadership skills and four conditions required for consistent skill development. Combining Vygotsky's theory of proximal development with identified transdisciplinary skills, we explain why educational scaffolding is needed to enable more successful design and delivery of transdisciplinary learning, particularly in One Health educational programs.
Making the Connection Between Theories of Policy Change and Policy Practice: A New Conceptualization
Authors: Feldman Guy
Published: June 2019

Over the past few decades, powerful economic, political and cultural forces have restructured the welfare state and social work practice. In response, there have been calls in recent years for the re-politicisation of the social work profession. One of the main ways in which social work has been re-politicised is through the emphasis on social workers’ involvement in the policy arena, commonly referred to as ‘policy practice’ in the literature. Although policy practice has recently received close attention in social work debates, it has remained relatively under-theorised. This article introduces social work scholars and practitioners to the theoretical work on policy change and elaborates its implications for how social workers can influence policy. Drawing on diverse literatures from the fields of political science and sociology, the article circumscribes to four influential theories of policy change that provide support for informed action in the policy arena: neo-institutional theory, elite theory, resource mobilisation theory and interdependent power theory. Drawing on these theories, the article develops a conceptualisation of four different types of policy practice: institutional policy practice, elite policy practice, resource-based policy practice and radical policy practice.
Neurotechnology-aided interventions for upper limb motor rehabilitation in severe chronic stroke
Authors: Coscia Martina , Wessel Maximilian J , Chaudary Ujwal , Millán José del R , Micera Silvestro , Guggisberg Adrian , Vuadens Philippe , Donoghue John , Birbaumer Niels , Hummel Friedhelm C
Published: June 2019

Upper limb motor deficits in severe stroke survivors often remain unresolved over extended time periods. Novel neurotechnologies have the potential to significantly support upper limb motor restoration in severely impaired stroke individuals. Here, we review recent controlled clinical studies and reviews focusing on the mechanisms of action and effectiveness of single and combined technology-aided interventions for upper limb motor rehabilitation after stroke, including robotics, muscular electrical stimulation, brain stimulation and brain computer/machine interfaces. We aim at identifying possible guidance for the optimal use of these new technologies to enhance upper limb motor recovery especially in severe chronic stroke patients. We found that the current literature does not provide enough evidence to support strict guidelines, because of the variability of the procedures for each intervention and of the heterogeneity of the stroke population. The present results confirm that neurotechnology-aided upper limb rehabilitation is promising for severe chronic stroke patients, but the combination of interventions often lacks understanding of single intervention mechanisms of action, which may not reflect the summation of single intervention’s effectiveness. Stroke rehabilitation is a long and complex process, and one single intervention administrated in a short time interval cannot have a large impact for motor recovery, especially in severely impaired patients. To design personalized interventions combining or proposing different interventions in sequence, it is necessary to have an excellent understanding of the mechanisms determining the effectiveness of a single treatment in this heterogeneous population of stroke patients. We encourage the identification of objective biomarkers for stroke recovery for patients’ stratification and to tailor treatments. Furthermore, the advantage of longitudinal personalized trial designs compared to classical double-blind placebo-controlled clinical trials as the basis for precise personalized stroke rehabilitation medicine is discussed. Finally, we also promote the necessary conceptual change from ‘one-suits-all’ treatments within in-patient clinical rehabilitation set-ups towards personalized home-based treatment strategies, by adopting novel technologies merging rehabilitation and motor assistance, including implantable ones.
Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases
Authors: Betts Matthew J , Kirilina Evgeniya , Otaduy Maria C G , Ivanov Dimo , Acosta-Cabronero Julio , Callaghan Martina F , Lambert Christian , Cardenas-Blanco Arturo , Pine Kerrin , Passamonti Luca , Loane Clare , Keuken Max C , Trujillo Paula , Lüsebrink Falk , Mattern Hendrik , Liu Kathy Y , Priovoulos Nikos , Fliessbach Klaus , Dahl Martin J , Maaß Anne , Madelung Christopher F , Meder David , Ehrenberg Alexander J , Speck Oliver , Weiskopf Nikolaus , Dolan Raymond , Inglis Ben , Tosun Duygu , Morawski Markus , Zucca Fabio A , Siebner Hartwig R , Mather Mara , Uludag Kamil , Heinsen Helmut , Poser Benedikt A , Howard Robert , Zecca Luigi , Rowe James B , Grinberg Lea T , Jacobs Heidi I L , Düzel Emrah , Hämmerer Dorothea
Published: June 2019

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.
Automated Canine Scent-Detection Apparatus: Technical Description and Training Outcomes
Authors: Edwards Timothy L
Published: June 2019

To date, laboratory scent-detection work with dogs has been a manual process whereby some or all aspects of the procedures are mediated by researchers. Automation of this process would eliminate issues associated with cuing, subjectivity in data collection, and reinforcement delivery. Herein, I describe an automated apparatus that can accommodate almost any type of sample that can be brought into the laboratory. The apparatus consists of a 17-segment carousel that rotates behind a panel. Dogs can access a single sample at a time through a port in the panel. Infrared beams are used to detect sample observations and indications, and a dog-activated switch is used to advance the carousel to the next sample. Correct indications are reinforced with an automated feeder. After screening 12 dogs, 5 dogs were selected and trained to use the apparatus to classify samples containing amyl acetate. All dogs achieved hit rates and correct rejection rates at or near 100% in fewer than 25 half-days of training (mean: 19.6, range: 12–24). These data suggest that the apparatus can be used to obtain accurate sample classification without excessive training requirements. Future improvements to the apparatus and training protocols may reduce the training requirements further.
Ionic Liquid-based Hollow Fiber Liquid–Liquid–Liquid Microextraction Combined with Capillary Electrophoresis for the Determination of Sulfonamides in Aquaculture Waters
Authors: Wu Youyi , Zhou Jingwen , Wang Xuedong , Zhang Zhanen , Gao Shiqian
Published: June 2019

Ionic liquid-based hollow-fiber liquid–liquid–liquid microextraction (IL-HF-LLLME) coupled to capillary electrophoresis (CE) has been developed for the determination of six sulfonamides (SAs) in aquaculture waters. A series of extraction parameters was optimized to enhance the extraction efficiency, which included type and pore size of hollow fiber, type and composition of extraction solvent, pH value of donor phase, the concentration of acceptor phase and the mass ratio of donor phase to acceptor phase along with extraction temperature and time. Under optimal conditions, the IL-HF-LLLME-CE method provided a wide liner range for six SAs from 2 to 1,000 μg L−1 (r2 ≥ 0.9995), the limits of the detection from 0.25 to 0.48 and the enrichment factors from 122 to 230, respectively. Relative standard deviations for intra- and interday precision were 1.4–5.3% and 1.8–7.5% (n = 5), respectively. The proposed method was successfully applied for the determination of trace-level SAs in seven real-world aquaculture water samples with good recoveries (80.4–100.7%). Also, sulfamerazine and sulfamethoxazole were detected at the level of 0.52–1.60 μg L−1 in two water samples. Due to its good sensitivity, simple operation, short analysis time and eco-friendliness, the developed method has a great application potential in analysis of trace SA residues in aquaculture waters.
(Re)membering Sara Baartman, Venus, and Aphrodite
Authors: Derbew Sarah
Published: June 2019

This article analyses the Black diasporic reception of Venus in the figure of Sara Baartman, a South African woman who performed under the name ‘Hottentot Venus’ in the early nineteenth century, and her theatrical persona in Suzan-Lori Parks’s play Venus [1990] (1997). Through her sophisticated characterization of Sara Baartman, Parks provides insight into the complex performativity of Black femalehood in conjunction with an overwritten Greco-Roman divinity. Parks’s play presents Sara Baartman as a person who forces her audiences, both theatrical and historical, to contend with their own complicit role in her objectification. More broadly, this cross-cultural dialogue attempts to recuperate the Black female subject from lopsided archives. It also contributes to a larger dismantling of the perceived boundaries between Greco-Roman art, African history, and African American literature.
Altererythrobacter rubellus sp. nov., a marine alphaproteobacterium isolated from seawater
Authors: Yoon Jaewoo , Ryu Jaewon
Published: June 2019

The phylogenetic and taxonomic status of an alphaproteobacterium isolated from seawater, collected in the Republic of Korea, was elucidated based on a polyphasic method. Strain KMU-45T was Gram-stain-negative, strictly aerobic, rod-shaped, non-motile and chemoheterotrophic. Phylogenetic investigation based on the 16S rRNA gene sequence demonstrated that the novel marine isolate belongs to the family Erythrobacteraceae, of the class Alphaproteobacteria, and that it possessed the highest (98.7%) sequence similarity with Altererythrobacter ishigakiensis ATCC BAA-2084T. DNA–DNA hybridization values between strains KMU-45T and A. ishigakiensis KCTC 42446T were 31.4% ± 8.4%. The major isoprenoid quinone of the novel isolate was ubiquinone-10 (Q-10) and the major (>10%) cellular fatty acids were C17:1 ω8c, C17:1 ω6c and C18:1 ω7c. The genomic DNA G + C content of strain KMU-45T was 57.7 mol%. The polar lipid profile of the strain KMU-45T comprised phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, an unidentified phospholipid and an unidentified lipid. From the polyphasic taxonomic results in this study, the bacterium can be considered to represent a new species of the genus Altererythrobacter, for which the name Altererythrobacter rubellus sp. nov. is proposed. The type species is A. rubellus sp. nov., with the type strain KMU-45T (= KCCM 90270T = NBRC 112769T).
Evaluation of a PGP3 ELISA for surveillance of the burden of Chlamydia infection in women from Australia and Samoa
Authors: Mazraani Rami , Timms Peter , Hill Philip C , Suaalii-Sauni Tamaailau , Niupulusu Tavita , Temese Seiuli V A , Iosefa-Siitia Liai , Auvaa Leveti , Tapelu Siuomatautu A , Motu Maauga F , Righarts Antoinette , Walsh Michael S , Rombauts Luk , Allan John A , Horner Patrick , Huston Wilhelmina M
Published: June 2019

Serological assays can be used to investigate the population burden of infection and potentially sequelae from Chlamydia. We investigated the PGP3 ELISA as a sero-epidemiological tool for infection or sub-fertility in Australian and Samoan women. The PGP3 ELISA absorbance levels were compared between groups of women with infertility, fertile, and current chlamydial infections. In the Australian groups, women with chlamydial tubal factor infertility had significantly higher absorbance levels in the PGP3 ELISA compared to fertile women (P < 0.0001), but not when compared to women with current chlamydial infection (P = 0.44). In the Samoan study, where the prevalence of chlamydial infections is much higher there were significant differences in the PGP3 ELISA absorbance levels between chlamydial sub-fertile women and fertile women (P = 0.003). There was no difference between chlamydial sub-fertile women and women with a current infection (P = 0.829). The results support that the PGP3 assay is effective for sero-epidemiological analysis of burden of infection, but not for evaluation of chlamydial pathological sequelae such as infertility.
Bee Communities across Gap, Edge, and Closed-Canopy Microsites in Forest Stands with Group Selection Openings
Authors: Mullally Hannah L , Buckley David S , Fordyce James A , Collins Beverly , Kwit Charles
Published: June 2019

As insect pollinator populations continue to decline, it is essential to understand the impacts of anthropogenic activities, including forest management, on pollinator communities. Although multiple studies have shown that clearcutting is beneficial for bees, other less intense, selective silvicultural methods that result in disproportionate increases in edge habitat within stands are less well understood. We investigated bee community characteristics across microsites (center of cut, edge of cut, and closed-canopy forest) in three mixed-mesophytic forest stands subjected to group selection cuttings. Results revealed bee communities in the center of cuts and their edges to differ from those in forest microsites, and their diversity measures were higher than in forest microsites. Within-stand edge microsites did not differ from their cut centers in terms of their communities or their diversity. Finally, center of cut and edge microsites combined, and forest microsites, were characterized by different indicator species, thereby exemplifying differences between these two microsite groupings. These results suggest that group selection harvests support differing communities of bees across microsites and sustain a wide range of bee species, and that edges within these forest stands behaved more like extensions of canopy gap openings despite differences in forest physiognomy.
Modeling Dominant Height Growth of Cedar (Cedrus libani A. Rich) Stands in Turkey
Authors: Özçelik Ramazan , Cao Quang V , Gómez-García Esteban , Crecente-Campo Felipe , Eler Ünal
Published: June 2019

Sustainable forest management requires accurate prediction from a growth and yield system. Such a system relies heavily on some measure of site productivity, which is often the site index. A model was developed for predicting dominant height growth and site index of even-aged cedar (Cedrus libani A. Rich.) stands in Turkey. Stem-analysis data from 148 trees were used for model development and validation. Six dynamic height–age equations were derived using the generalized algebraic difference approach (GADA). Autocorrelation was modeled by expanding the error term as an autoregressive process. Based on numerical and graphical analysis, a GADA formulation derived from the Chapman–Richards model was selected. Based on relative error in dominant height prediction, 80 years was selected as the best reference age. The resulting equation provided the best compromise between biological and statistical aspects and, therefore, is recommended for height growth prediction and site classification of cedar stands in Turkey.
Characterization and immunogenicity of a Shigella flexneri 2a O-antigen bioconjugate vaccine candidate
Authors: Ravenscroft Neil , Braun Martin , Schneider Joerg , Dreyer Anita M , Wetter Michael , Haeuptle Micha A , Kemmler Stefan , Steffen Michael , Sirena Dominique , Herwig Stefan , Carranza Paula , Jones Claire , Pollard Andrew J , Wacker Michael , Kowarik Michael
Published: June 2019

Shigellosis remains a major cause of diarrheal disease in developing countries and causes substantial morbidity and mortality in children. Vaccination represents a promising preventive measure to fight the burden of the disease, but despite enormous efforts, an efficacious vaccine is not available to date. The use of an innovative biosynthetic Escherichia coli glycosylation system substantially simplifies the production of a multivalent conjugate vaccine to prevent shigellosis. This bioconjugation approach has been used to produce the Shigella dysenteriae type O1 conjugate that has been successfully tested in a phase I clinical study in humans. In this report, we describe a similar approach for the production of an additional serotype required for a broadly protective shigellosis vaccine candidate. The Shigella flexneri 2a O-polysaccharide is conjugated to introduced asparagine residues of the carrier protein exotoxin A (EPA) from Pseudomonas aeruginosa by co-expression with the PglB oligosaccharyltransferase. The bioconjugate was purified, characterized using physicochemical methods and subjected to preclinical evaluation in rats. The bioconjugate elicited functional antibodies as shown by a bactericidal assay for S. flexneri 2a. This study confirms the applicability of bioconjugation for the S. flexneri 2a O-antigen, which provides an intrinsic advantage over chemical conjugates due to the simplicity of a single production step and ease of characterization of the homogenous monomeric conjugate formed. In addition, it shows that bioconjugates are able to raise functional antibodies against the polysaccharide antigen.
Recent advances in molecular therapies for neurological disease: triplet repeat disorders
Authors: Gonzalez-Alegre Pedro
Published: June 2019

Triplet repeat diseases (TRDs) are caused by pathogenic expansions of trinucleotide sequence repeats within coding and non-coding regions of different genes. They are typically progressive, very disabling and frequently involve the nervous system. Currently available symptomatic therapies provide modest benefit at best. The development of interventions that interfere with the natural history of these diseases is a priority. A common pathogenic process shared by most TRDs is the presence of toxicity from the messenger RNA or protein encoded by the gene harboring the abnormal expansion. Strategies to interfere with the expression of these genes using different molecular approaches are being pursued and have reached the clinical stage. This review will summarize the significant progress made in this field in the last few years, focusing on three main areas: the discovery of biomarkers of disease progression and target engagement, advances in preclinical studies for the polyglutamine ataxias and the initial clinical application in myotonic dystrophy type 1 and Huntington’s disease.
Progress and challenges in development of new therapies for urea cycle disorders
Authors: Soria Leandro R , Ah Mew Nicholas , Brunetti-Pierri Nicola
Published: June 2019

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to transfer nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and orthotopic liver transplantation. In the last years, there has been intense preclinical research aiming at developing more effective treatments for UCD, and as a result, several novel approaches based on new knowledge of the disease pathogenesis, cell and gene therapies are currently under clinical investigation. We provide an overview of the latest advances for the development of novel therapies for UCD.
Proactive Vs Reactive Therapeutic Drug Monitoring of Infliximab in Crohn’s Disease: A Cost-Effectiveness Analysis in a Simulated Cohort
Authors: Negoescu Diana M , Enns Eva A , Swanhorst Brooke , Baumgartner Bonnie , Campbell James P , Osterman Mark T , Papamichael Konstantinos , Cheifetz Adam S , Vaughn Byron P
Published: June 2019

Proactive therapeutic drug monitoring of infliximab is a marginally cost-effective strategy for Crohn’s disease, whereas reactive therapeutic drug monitoring is cost-effective. As the cost of infliximab decreases, a proactive strategy of dosing infliximab becomes more cost-effective.
Cyber Gremlin: social networking, machine learning and the global war on Al-Qaida-and IS-inspired terrorism
Authors: Ammar Jamil
Published: June 2019

Among our mundane and technical concepts, machine learning is currently one of the most important and widely used, but least understood. To date, legal scholars have conducted comparatively little work on its cognate concepts. This article critically examines the use of machine learning technologies to suppress or block access to al-Qaida and IS-inspired propaganda. It will: (i) demonstrate that, insofar as law and policy dictate that machine learning systems comply with desired constitutional norms, automated-decision making systems are not as effective as critics would like; (ii) emphasize that, under the current envisaged ‘proactive’ role of networking sites, equating radical and extreme ideas and ideology with ‘violence’ is a practical reality; and (iii) outline a workable strategy for cross-border legal and technical counterterrorism that satisfies the requirements for algorithmic fairness.
Comment on: An Insight Into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions
Authors: Jouanjus Emilie , Micallef Joëlle , Mallaret Michel , Lapeyre-Mestre Maryse
Published: June 2019

After the publication of an article discussing the methodological options to detect the diversion potential of prescription drugs, this letter presents the multidimensional functioning of the French Addictovigilance System. This system aims at monitoring all substances with abuse potential, relying on a network of experts specialized in clinical and fundamental pharmacology. For more than 25 years, we have created collaborations with partners at the interface with field data related to substance use and the potential related disorders. When relevant depending on the context, these data sources are explored and crossed to analyze the abuse potential of one given substance. This organizational approach is useful to detect early Addictovigilance warning signals and to take appropriate measures. Generalizing such a multidimensional approach outside France appears an appealing option to move towards more effective Addictovigilance systems at the international level.
Lyapunov regularity and stability of linear non-instantaneous impulsive differential systems
Authors: Wang JinRong , Li Mengmeng , O’Regan Donal
Published: June 2019

In this paper, we discuss Lyapunov regularity and stability for linear non-instantaneous impulsive differential systems. In particular, we give sufficient conditions to guarantee any non-trivial solution has a finite Lyapunov exponent and we prove an impulsive system is stable using the Lyapunov exponent for the solution. A new version of Perron’s theorem is given by introducing the associated adjoint impulsive system and some criteria for the existence of non-uniform exponential behaviour are given. In addition, we present a stability result for a small perturbed nonlinear impulsive system when the linear impulsive system admits a non-uniform exponential contraction. Finally, we give a bound for the regularity coefficient.
Geometric quantization of localized surface plasmons
Authors: Schnitzer Ory
Published: June 2019

We consider the quasi-static problem governing the localized surface plasmon modes and permittivity eigenvalues $\epsilon $ of smooth, arbitrarily shaped, axisymmetric inclusions. We develop an asymptotic theory for the dense part of the spectrum, i.e. close to the accumulation value $\epsilon =-1$ at which a flat interface supports surface plasmons; in this regime, the field oscillates rapidly along the surface and decays exponentially away from it on a comparable scale. With $\tau =-(\epsilon +1)$ as the small parameter, we develop a surface-ray description of the eigenfunctions in a narrow boundary layer about the interface; the fast phase variation, as well as the slowly varying amplitude and geometric phase, along the rays are determined as functions of the local geometry. We focus on modes varying at most moderately in the azimuthal direction, in which case the surface rays are meridian arcs that focus at the two poles. Asymptotically matching the diverging ray solutions with expansions valid in inner regions in the vicinities of the poles yields the quantization rule \begin{equation*}\frac{1}{\tau} \sim \frac{\pi n }{\varTheta}+\frac{1}{2}\left(\frac{\pi}{\varTheta}-1\right)+o(1),\end{equation*}where $n\gg 1$ is an integer and $\varTheta $ a geometric parameter given by the product of the inclusion length and the reciprocal average of its cross-sectional radius along its symmetry axis. For a sphere, $\varTheta =\pi $, whereby the formula returns the exact eigenvalues $\epsilon =-1-1/n$. We also demonstrate good agreement with exact solutions in the case of prolate spheroids.
Dynamic backstepping control for pure-feedback non-linear systems
Authors: Zhang Sheng , Yong En-Mi , Zhou Yu , Qian Wei-Qi
Published: June 2019

A dynamic backstepping control method is proposed for non-linear systems in the pure-feedback form, for which the traditional backstepping method suffers from solving the implicit non-linear algebraic equation. This method treats the implicit algebraic equation directly via a dynamic way, by augmenting the (virtual) controls as states during each recursive step. Compared with the traditional backstepping method, one more Lyapunov design is executed in each step. As new dynamics are included in the design, the resulting control law is in the dynamic feedback form. Under appropriate assumptions, the proposed control scheme achieves the uniformly asymptotic stability and the closed-loop system is local input-to-state stable for various disturbance. Moreover, the control law may be simplified to the inverse-free form by setting large gains, which will alleviate the problem of `explosion of terms’. The effectiveness of this method is illustrated by the stabilization and tracking numerical examples.
A Lawson-type exponential integrator for the Korteweg–de Vries equation
Authors: Ostermann Alexander , Su Chunmei
Published: June 2019

We propose an explicit numerical method for the periodic Korteweg–de Vries equation. Our method is based on a Lawson-type exponential integrator for time integration and the Rusanov scheme for Burgers’ nonlinearity. We prove first-order convergence in both space and time under a mild Courant–Friedrichs–Lewy condition $\tau =O(h)$, where $\tau$ and $h$ represent the time step and mesh size for solutions in the Sobolev space $H^3((-\pi , \pi ))$, respectively. Numerical examples illustrating our convergence result are given.
Supporting Inclusion, Diversity, Access, and Equity in the Infectious Disease Workforce
Authors: Marcelin Jasmine R , Manne-Goehler Jennifer , Silver Julie K
Published: June 2019

In medicine, a wide array of evidence demonstrates the presence of gender, racial, ethnic, and other disparities in representation, compensation, and career development. These disparities also exist in the field of infectious diseases, providing important opportunities for the Infectious Diseases Society of America to identify and report its successes in and challenges to achieving equity. In this article, we review the literature documenting challenges with equity broadly in medicine and specifically in infectious diseases. We then introduce the Be Ethical Campaign, an initiative that encourages healthcare leaders to use metrics and data analysis to identify workforce equity gaps and pursue opportunities to close them.
Identification of Widespread Antibiotic Exposure in Patients With Cholera Correlates With Clinically Relevant Microbiota Changes
Authors: Alexandrova Ludmila , Haque Farhana , Rodriguez Patricia , Marrazzo Ashton C , Grembi Jessica A , Ramachandran Vasavi , Hryckowian Andrew J , Adams Christopher M , Siddique Md Shah A , Khan Ashraful I , Qadri Firdausi , Andrews Jason R , Rahman Mahmudur , Spormann Alfred M , Schoolnik Gary K , Chien Allis , Nelson Eric J
Published: June 2019

Background

A first step to combating antimicrobial resistance in enteric pathogens is to establish an objective assessment of antibiotic exposure. Our goal was to develop and evaluate a liquid chromatography–ion trap mass spectrometry (LC/MS) method to determine antibiotic exposure in patients with cholera.

Methods

A priority list for targeted LC/MS was generated from medication-vendor surveys in Bangladesh. A study of patients with and those without cholera was conducted to collect and analyze paired urine and stool samples.

Results

Among 845 patients, 11% (90) were Vibrio cholerae positive; among these 90 patients, analysis of stool specimens revealed ≥1 antibiotic in 86% and ≥2 antibiotics in 52%. Among 44 patients with cholera and paired urine and stool specimens, ≥1 antibiotic was detected in 98% and ≥2 antibiotics were detected in 84%, despite 55% self-reporting medication use. Compared with LC/MS, a low-cost antimicrobial detection bioassay lacked a sufficient negative predictive value (10%; 95% confidence interval, 6%–16%). Detection of guideline-recommended antibiotics in stool specimens did (for azithromycin; P = .040) and did not (for ciprofloxacin) correlate with V. cholerae suppression. A nonrecommended antibiotic (metronidazole) was associated with decreases in anaerobes (ie, Prevotella organisms; P < .001).

Conclusion

These findings suggest that there may be no true negative control group when attempting to account for antibiotic exposure in settings like those in this study.
An Initial Model of Trust in Chatbots for Customer Service—Findings from a Questionnaire Study
Authors: Nordheim Cecilie Bertinussen , Følstad Asbjørn , Bjørkli Cato Alexander
Published: June 2019

Chatbots are predicted to play a key role in customer service. Users’ trust in such chatbots is critical for their uptake. However, there is a lack of knowledge concerning users’ trust in chatbots. To bridge this knowledge gap, we present a questionnaire study (N = 154) that investigated factors of relevance for trust in customer service chatbots. The study included two parts: an explanatory investigation of the relative importance of factors known to predict trust from the general literature on interactive systems and an exploratory identification of other factors of particular relevance for trust in chatbots. The participants were recruited as part of their dialogue with one of four chatbots for customer service. Based on the findings, we propose an initial model of trust in chatbots for customer service, including chatbot-related factors (perceived expertise and responsiveness), environment-related factors (risk and brand perceptions) and user-related factors (propensity to trust technology).

RESEARCH HIGHLIGHTS

We extend the current knowledge base on natural language interfaces by investigating factors affecting users’ trust in chatbots for customer service. Chatbot-related factors, specifically perceived expertise and responsiveness, are found particularly important to users’ trust in such chatbots, but also environment-related factors such as brand perception and user-related factors such as propensity to trust technology. On the basis of the findings, we propose an initial model of users’ trust chatbots for customer service.
Pneumococcal susceptibility to antibiotics in carriage: a 17 year time series analysis of the adaptive evolution of non-vaccine emerging serotypes to a new selective pressure environment
Authors: Ouldali Naim , Cohen Robert , Levy Corinne , Gelbert-Baudino Nathalie , Seror Elisa , Corrard François , Vie Le Sage François , Michot Anne-Sylvestre , Romain Olivier , Bechet Stéphane , Bonacorsi Stéphane , Angoulvant François , Varon Emmanuelle
Published: June 2019

Background

Pneumococcal conjugate vaccine (PCV) implementations led to major changes in serotype distribution and antibiotic resistance in carriage, accompanied by changes in antibiotic consumption.

Objectives

To assess the dynamic patterns of antimicrobial non-susceptibility across non-PCV13 serotypes following PCV implementations.

Methods

We conducted a quasi-experimental interrupted time series analysis based on a 17 year French nationwide prospective cohort. From 2001 to 2018, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media who were aged 6 months to 2 years. The main outcome was the rate of penicillin-non-susceptible pneumococci (PNSP), analysed by segmented regression.

Results

We enrolled 10 204 children. After PCV13 implementation, the PNSP rate decreased (−0.5% per month; 95% CI −0.9 to −0.1), then, after 2014, the rate slightly increased (+0.7% per month; 95% CI +0.2 to +1.2). Global antibiotic use within the previous 3 months decreased over the study period (−22.2%; 95% CI −33.0 to −11.3), but aminopenicillin use remained high. Among the main non-PCV13 serotypes, four dynamic patterns of penicillin susceptibility evolution were observed, including unexpected patterns of serotypes emerging while remaining or even becoming penicillin susceptible. In contrast to PNSP strains, for these latter patterns, the rate of co-colonization with Haemophilus influenzae increased concomitant with their emergence.

Conclusions

In a context of continuing high antibiotic selective pressure, a progressive increase in PNSP rate was observed after 2014. However, we highlighted an unexpected variability in dynamic patterns of penicillin susceptibility among emerging non-PCV13 serotypes. Antibiotic resistance may not be the only adaptive mechanism to antimicrobial selective pressure, and co-colonization with H. influenzae may be involved.
Characterization of the human E2F4 promoter region and its response to 12-O-tetradecanoylphorbol-13-acetate
Authors: Hamada Hiroshi , Goto Yuta , Arakawa Jun , Murayama Erisa , Ogawa Yui , Konno Midori , Oyama Takahiro , Asai Masashi , Sato Akira , Tanuma Sei-ichi , Uchiumi Fumiaki
Published: June 2019

The E2F transcription factors (TFs), which control the progression of the cell cycle in response to DNA-damage and various stresses, are known to interact with a tumour suppressor, Retinoblastoma 1 (RB1). We previously showed that the response of the human RB1 promoter to a 12-O-tetradecanoylphorbol-13-acetate (TPA) in HL-60 cells is mediated by a duplicated GGAA motif, which is also present in the 5′-upstream of the E2F family genes. The motifs are especially rich in the 5′-upstream of the E2F4 gene. In the present study, we constructed luciferase (Luc) expression vectors containing a 466 bp of the 5′-upstream of the human E2F4 gene. The transfection of this plasmid and deletion/mutation-introduced derivatives into HL-60 cells and a Luc reporter assay showed that duplicated and triplicated GGAA (TTCC) motifs in the E2F4 promoter respond to TPA. As expected, electrophoretic mobility shift assay indicated that SPI1 (PU.1) binds to the GGAA motif-containing element. A quantitative RT-PCR and western blotting showed that the E2F4 transcripts and its encoding proteins accumulate during the differentiation of HL-60 into macrophage-like cells. In contrast, the expression of the E2F1 gene and the protein, which possibly acts as a cell cycle accelerator, was greatly diminished.