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Abstract Background Chronic myeloid leukemia is associated with a BCR/ABL oncoprotein inhibited by imatinib mesylate, the first tyrosine kinase inhibitor. Although experimental studies have clearly demonstrated the efficacy of imatinib, up-to-date data on its effectiveness at the population level are limited. Our study aims to assess the change in disease-specific survival for chronic myeloid leukemia after introducing tyrosine kinase inhibitors in first-line treatment. Methods This study analyzed data from two population-based cancer registries in Italy. Disease-specific survival for chronic myeloid leukemia cases diagnosed before and after the introduction of tyrosine kinase inhibitors (February 2002) were calculated up to 10 years. Hazard ratios were calculated using Cox regression models adjusted for sex, age at diagnosis and residency. An interrupted time series analysis was also performed. Results Between 1996 and 2012, 357 new cases of chronic myeloid leukemia were diagnosed (standardized incidence rate of 1.2 per 100,000 residents), quite constant throughout the period. The interrupted time series analysis showed a gain of 40.4% in 5 years of disease-specific survival for chronic myeloid leukemia (from 47.3, 95%CI 38.5–55.5% to 80.8%, 95%CI 74.5–85.8%) after the introduction of tyrosine kinase inhibitors. The hazard ratio was 0.36 (95%CI 0.25–0.52) for cases diagnosed after tyrosine kinase inhibitor introduction, with differences per age at diagnosis: 74yo 0.41 (95%CI 0.23–0.73). An improvement in survival (hazard ratio 0.66, 95%CI 0.36–1.20) was also observed in cases diagnosed before, and alive at, tyrosine kinase inhibitors introduction. Conclusions Tyrosine kinase inhibitors increased disease-specific survival both for new and prevalent chronic myeloid leukemia cases. The effectiveness was similar to that observed in trials only in patients ages 65 years or younger.

The short editorial introduces the new issue and volume of the Review. In this issue, the PSL Quarterly Review is relaunching the “Recollections of Eminent Economists” series, which used to be published in both English and Italian, respectively in BNL Quarterly Review and Moneta e Credito. The “Recollections of Eminent Economists” series was launched in 1978, with the first article in September 1978 by John Hicks. The Recollections were intended as a series of autobiographies of intellectuals. Authors invited to contribute were allowed full liberty of topic and scope. ). As before, authors invited to contribute to the new series are granted the maximum creative liberty; the articles may be autobiographical, or consist in reflections on their research, or, more generally, on economics as a discipline. The first inaugural contribution published in this issue is by board member A.P. Thirlwall.

RESUMO O artigo verifica a hipótese de homogeneidade estrita do pensamento estruturalista latino-americano em matéria de estabilidade monetária em seus anos iniciais. Em meados da década de 1950, o crescente e contínuo fenômeno inflacionário na região era explicado pela CEPAL como resultante da presença de estrangulamentos nas estruturas reais da economia. Entretanto, o canal de transmissão ao nível de preços é explicado pelos autores de maneiras diversas, gerando-se, por conseguinte, diferentes propostas de estabilização. O artigo sublinha a flexibilidade metodológica e o grau de fragmentação teórica da abordagem cepalina, bem como a controvérsia sobre a inflação constituir parte do processo de desenvolvimento. A análise destes elementos revela uma tensão entre os aspectos keynesianos anglo-saxônicos na abordagem de Prebisch e a original teoria latino-americana proposta por Noyola e Furtado. Avalia-se em que medida este descompasso impediu a constituição de um corpo teórico diferenciado em matéria de estabilização monetária.

The short editorial introduces the new volume and provides information on the new composition of the board of editors. Starting from this issue, the main responsibility for editing the two journals "Moneta e Credito" and "PSL Quarterly Review" shifts from Alessandro Roncaglia to Carlo D’Ippoliti. Roncaglia, chairman of Economia Civile, which publishes both journals, remains on the board as co-editor. The present introduction explains the main reasons for this change, and shortly recalls the recent history of the Review.

Despite differences in their function and domain-specific elements, syntactic processing in music and language is believed to share cognitive resources. This study aims to investigate whether the simultaneous processing of language and music share the use of a common syntactic processor or more general attentional resources. To investigate this matter we tested musicians and non-musicians using visually presented sentences and aurally presented melodies containing syntactic local and long-distance dependencies. Accuracy rates and reaction times of participants’ responses were collected. In both sentences and melodies, unexpected syntactic anomalies were introduced. This is the first study to address the processing of local and long-distance dependencies in language and music combined while reducing the effect of sensory memory. Participants were instructed to focus on language (language session), music (music session), or both (dual session). In the language session, musicians and non-musicians performed comparably in terms of accuracy rates and reaction times. As expected, groups’ differences appeared in the music session, with musicians being more accurate in their responses than non-musicians and only the latter showing an interaction between the accuracy rates for music and language syntax. In the dual session musicians were overall more accurate than non-musicians. However, both groups showed comparable behavior, by displaying an interaction between the accuracy rates for language and music syntax responses. In our study, accuracy rates seem to better capture the interaction between language and music syntax; and this interaction seems to indicate the use of distinct, however, interacting mechanisms as part of decision making strategy. This interaction seems to be subject of an increase of attentional load and domain proficiency. Our study contributes to the long-lasting debate about the commonalities between language and music by providing evidence for their interaction at a more domain-general level.

The paper analyzes the shortcomings of the Real Plan combining political science and economics, considering evidences on difficulties in implementing a complete plan of deindexation, namely: the distributional conflict, the corporatist relations between the State and society and the bureaucratic isolation of a highly specialized technocracy. The announcement of the plan triggered defensive reactions, fueling distributive tensions during the URV period, forcing the economic team to take measures that contradicted the overall guidelines followed. The persistence of indexation mechanisms indicate the resulting obstacles in seeking a reform of the State through a stabilization plan, even though the latter has the former as a precondition.

L’intervento riflette sull’utilizzo dell’etnografia visiva come sapere nomade (in senso fisico e riflessivo) per documentare il lavoro delle donne nell’agricoltura lombarda. Un sapere tecnico e antropologico che, durante le ricerche sul campo, parte dalle definizioni che le donne danno di sé per descrivere e raccontare le proprie esperienze professionali in relazione a contesti relazionali più ampi: la famiglia, il contesto geografico, abitativo, sociale e culturale. Lo strumento dell’intervista non strutturata dall’andamento biografico ha perciò proprio lo scopo di restituire quanto più possibile il punto di vista dell’intervistata e di consentire, nell’incontro riflessivo che si viene a creare, la costruzione di un archivio “vivo”.

With the financialization of the economy, increasing reliance has been put on statistical models for derivatives pricing and for risk assessment in the day-to-day business of financial operators as well as in financial regulation. This practice had already been criticized from many quarters and on different accounts before the crisis, but these criticisms were simply ignored by the prevailing consensus. This work reconsiders such criticisms from a different standpoint: though they are justified, they could have been put forward in even stronger terms had they relied on Keynes’s work on probability and his notion of uncertainty. I shall thus focus on the conceptual views underlying statistical risk assessment techniques rather than on the techniques in themselves. Finally, I set out some policy implications for regulation.

In continuation of our work on supramolecular architectures of single-molecule magnets (SMMs) as a promising strategy in developing their magnetic performance, in this paper we report the synthesis and single crystal X-ray structure of the centered triangular tetrairon(III) SMM, [Fe4(PhpPy)2(dpm)6], Fe4 (Hdpm = dipivaloylmethane, H3PhpPy = 2-(hydroxymethyl)-2-(4-(pyridine-4-yl)phenyl)propane-1,3-diol), and its assembly in the coordination polymer {[Fe4(PhpPy)2(dpm)6Ag](ClO4)}n, Fe4Ag, upon reaction with silver(I) perchlorate. Thanks to the presence of the pyridyl rings on the two tripodal ligands, Fe4 behaves as divergent ditopic linker, and due to the Fe4:AgClO4 1:1 ratio, Fe4Ag probably possesses a linear arrangement in which silver(I) ions are linearly coordinated by two nitrogen atoms, forming 1D chains whose positive charge is balanced by the perchlorate anions. The stabilization of such a polymeric structure can be ascribed to the long distance between the two donor nitrogen atoms (23.4 Å) and their donor power. Fe4Ag shows slow relaxation of the magnetization which follows a thermally activated process with Ueff/kB = 11.17(18) K, τ0 = 2.24(17) 10−7 s in zero field, and Ueff/kB = 14.49(5) K, τ0 = 3.88(8) 10−7 s in 1-kOe applied field, in line with what reported for tetrairon(III) SMMs acting as building blocks in polymeric structures.

OBJETIVO: Estudo experimental idealizado para investigar as propriedades mecânicas de tendões flexores profundos de coelhos submetidos à tenotomia seguida de tenorrafia e aplicação precoce de ultra-som terapêutico com diferentes intensidades, em comparação com tendões submetidos somente à tenorrafia. MATERIAL E MÉTODOS: Quarenta e quatro coelhos foram divididos em quatro grupos experimentais de acordo com a aplicação do ultra-som. Todos foram submetidos a uma secção do tendão flexor profundo na zona 2 e imobilizados com uma órtese mantida durante todo o experimento. O grupo A recebeu tratamento ultra-sônico com uma intensidade de 1,4 W/cm², o grupo B com 0,6 W/cm², ambos no modo contínuo, o grupo C com 0,6 W/cm² SATA, no modo pulsado à 50% e o grupo D não recebeu tratamento ultra-sônico algum. A frequência ultra-sônica empregada foi de 1 MHz. Após a eutanásia os tendões foram dissecados e submetidos ao ensaio mecânico de tração e análise histológica qualitativa. As propriedades mecânicas avaliadas foram: força máxima, deformação na força máxima e rigidez. RESULTADO: Não houve diferença estatisticamente significante entre os grupos experimentais. CONCLUSÃO: O ultra-som terapêutico não melhorou as propriedades mecânicas dos tendões flexores após reparo.OBJECTIVE: Experimental study idealized to investigate the mechanical properties of deep flexor tendons of rabbits that underwent the tenotomy followed by tenorrhaphy and early application of therapeutic ultrasound with different intensities, in comparison to tendons submitted to tenorrhaphy only. MATERIAL AND METHOD: Forty-four rabbits were divided into four experimental groups according to the ultrasound application. They were all submitted to a section of deep flexor tendon in zone 2 and immobilized with an orthosis maintained throughout the experiment. Group A received ultrasonic treatment with an intensity of 1.4 W/cm², group B with 0.6 W/cm², both in continuous mode, group C with 0.6 W/cm² SATA, in pulsated mode at 50% and group D did not receive any ultrasonic treatment. The ultrasonic frequency employed was 1 MHz. After euthanasia, the tendons were dissected and submitted to the mechanical test of traction and qualitative histological analysis. The evaluated mechanical properties were: maximum force, deformation in maximum force and stiffness. RESULTS: There were no statistically significant differences among the experimental groups. CONCLUSION: Therapeutic ultrasound did not improve the mechanical properties of the flexor tendons after repair.

The article introduces the first issue of the PSL Quarterly Review (formerly known as Banca Nazionale del Lavoro Quarterly Review, or simply BNL Quarterly Review). In this work, Alessandro Roncaglia, editor of the journal, summarizes and personally re-interprets the decades-long history of the journal and of its sister journal Moneta e Credito. Besides highlighting the major contributions that starting from the 1960s appeared in the journal, the article introduces the new series and lays down the foundations of the editorial policy.

Article originally published in the volume 59 issue 236 of Banca Nazionale del Lavoro Quarterly Review (also known as BNL Quarterly Review).

Luigi Ceriani (1912-1999) was the founder of Moneta e Credito and Banca Nazionale del Lavoro Quarterly Review, and their editor for the first forty years of their lives. The article illustrates his life history, in particular his role in the founding and in the successive life of the two journals as well as in the Banca Nazionale del Lavoro as director of its Economic Research Department.

Resumen Piero Sraffa (1898·1983) es considerado uno de los economistas más destacados de todos los tiempos. La solidez de su crítica a la teoría de Marshall de la empresa y al concepto marginalista del capital como factor de producción ha sido reconocida incluso por sus oponentes; en el campo de la historia del pensamiento económico no puede hacerse caso omiso de su interpretación de la obra de David Ricardo y de su reconstrucción del núcleo conceptual analítico del "enfoque del excedente"; en el campo de la teoría del valor los resultados de Producción de mercancías por medio de mercancías constituyen el punto de partida de cientos de trabajos. Este artículo presenta una visión general de la vida y la obra de este insigne economista italiano, destacando, en primer término, la importancia que en tal trabajo de Sraffa tuvieron Antonio Gramsci, Ludwig Wittgenstein y John Maynard Keynes; enseguida se exponen, de manera sintética, los principales aspectos de la Revolución Sraffiana. Abstract Piero Sraffa (1898-1983) is considered one of the most distinguished economists of all times. 771e solidity of his criticism to Marshall s theory of the firm and to the marginalist concept of capital, as a factor of production, has been acknowledged even by his opponents. In the field of economic thought we cannot omit his interpretation of David Ricardo's work and his reconstruction of the analytical core of the "surplus approach ". In the field of the theory of value the conclusions of Production of Commodities by Means of Commodities constitutes the point of departure of hundreds of works. This paper presents a general view of the life and work of this distinguished Italian economist. Firstly in underlines the influence of Antonio Cramsci, Ludwig Wittgenstein and John Maynard Keynes in the Sraffa's work and is followed by a synthetic exposition of the main aspects of the Sraffian Revolution. Palabras claves: Economía política, revolución Sraffiana.

Determine global gene dysregulation affecting 4q-linked (FSHD-1) and non 4q-linked (FSHD-2) cells during early stages of myogenic differentiation. This approach has been never applied to FSHD pathogenesis.By in vitro differentiation of FSHD-1 and FSHD-2 myoblasts and gene chip analysis we derived that gene expression profile is altered only in FSHD-1 myoblasts and FSHD-2 myotubes. The changes seen in FSHD-1 regarded a general defect in cell cycle progression, probably due to the upregulation of myogenic markers PAX3 and MYOD1, and a deficit of factors (SUV39H1 and HMGB2) involved in D4Z4 chromatin conformation. On the other hand, FSHD-2 mytubes were characterized by a general defect in RNA metabolism, protein synthesis and degradation and, to a lesser extent, in cell cycle. Common dysregulations regarded genes involved in response to oxidative stress and in sterol biosynthetic process. Interestingly, our results also suggest that miRNAs might be implied in both FSHD-1 and FSHD-2 gene dysregulation. Finally, in both cell differentiation systems, we did not observe a gradient of altered gene expression throughout the 4q35 chromosome.FSHD-1 and FSHD-2 cells showed, in different steps of myogenic differentiation, a global deregulation of gene expression rather than an alteration of expression of 4q35 specific genes. In general, FSHD-1 and FSHD-2 global gene deregulation interested common and distinctive biological processes. In this regard, defects of cell cycle progression (FSHD-1 and to a lesser extent FSHD-2), protein synthesis and degradation (FSHD-2), response to oxidative stress (FSHD-1 and FSHD-2), and cholesterol homeostasis (FSHD-1 and FSHD-2) may in general impair a correct myogenesis. Taken together our results recapitulate previously reported defects of FSHD-1, and add new insights into the gene deregulation characterizing both FSHD-1 and FSHD-2, in which miRNAs may play a role.

Retirement transitions in ballet dancers have been under researched. The purpose of this paper is to investigate the experiences of career transition in ballet dancers, from a life course perspective. Drawing upon existing transition models (SCHLOSSBERG, 1981) and sport literature (TAYLOR & OGILVIE, 1994), the paper investigates how ballet dancers cope (or not) with the transition and explores the different factors influencing the coping process. Qualitative analysis of semi-structured interviews from fourteen international ballet dancers were used adopting an idiographic approach through interpretative phenomenological analysis and tenets of grounded theory methodology. The results identified a main theme "Coping strategies: Coping within & without" and eight sub-categories: Denial, alienation, indecision, severance, acceptance, letting go, renegotiation and reconstruction. The individual can experience different responses, which trigger different coping processes and subsequently different types of support are sought. Finally the paper briefly discusses some of the implications for future career development and career guidance. URN: urn:nbn:de:0114-fqs100210

BACKGROUND: In diabetes chronic hyperinsulinemia contributes to the instability of the atherosclerotic plaque and stimulates cellular proliferation through the activation of the MAP kinases, which in turn regulate cellular proliferation. However, it is not known whether insulin itself could increase the transcription of specific genes for cellular proliferation in the endothelium. Hence, the characterization of transcriptional modifications in endothelium is an important step for a better understanding of the mechanism of insulin action and the relationship between endothelial cell dysfunction and insulin resistance. METHODOLOGY AND PRINCIPAL FINDINGS: The transcriptional response of endothelial cells in the 440 minutes following insulin stimulation was monitored using microarrays and compared to a control condition. About 1700 genes were selected as differentially expressed based on their treated minus control profile, thus allowing the detection of even small but systematic changes in gene expression. Genes were clustered in 7 groups according to their time expression profile and classified into 15 functional categories that can support the biological effects of insulin, based on Gene Ontology enrichment analysis. In terms of endothelial function, the most prominent processes affected were NADH dehydrogenase activity, N-terminal myristoylation domain binding, nitric-oxide synthase regulator activity and growth factor binding. Pathway-based enrichment analysis revealed "Electron Transport Chain" significantly enriched. Results were validated on genes belonging to "Electron Transport Chain" pathway, using quantitative RT-PCR. CONCLUSIONS: As far as we know, this is the first systematic study in the literature monitoring transcriptional response to insulin in endothelial cells, in a time series microarray experiment. Since chronic hyperinsulinemia contributes to the instability of the atherosclerotic plaque and stimulates cellular proliferation, some of the genes identified in the present work are potential novel candidates in diabetes complications related to endothelial dysfunction.

The short note introduces the articles published in this issue, placing the different contributions in the current socio-economic context.

In this article I will review four papers presented at the British Psychological Society Annual Conference held this year in London held over a 3 day period. The Conference included a variety of scientific presentations and discussions through symposia, roundtable discussions, single papers and poster sessions. Although numerous papers took an experimental approach, few applied any type of qualitative methodology. The topics covered within the different psychological disciplines spanned from early childhood through old age; I have chosen four papers that covered a life course perspective and took into consideration clinical issues as well. The first paper discusses a grounded theory approach used to analyse a play therapy session between therapist and child. The second review reports some recent findings in the way the brains of people on the autistic spectrum disorder might function. The third paper discusses positive psychology and how such an emerging movement has influenced new research in the field. The last paper reviewed will discuss the issue of the ageing process, and I will present some arguments related to the useful application of qualitative methodologies within this area of research. In conclusion, I will highlight some personal reflections on the Conference and the need for a greater balance between qualitative and quantitative methodologies to be used in collaboration rather than as antagonists. URN: urn:nbn:de:0114-fqs0402176

In this article the author reviews the one day Conference held in London at the British Library which provided an opportunity to discuss different ways of analysing and making sense of transcribed interviews using various approaches. These approaches have been discussed in order to assist researchers during the process of identi­fication of themes, through comparisons, analysis, and the drawing of conclusions. The debates which emerged included ways of analysing oral history data through participative approaches discussing issues around often sensitive topics. The report outlines the issues covered giving a critical summary of the event, which has helped to expose newcomers to oral history. URN: urn:nbn:de:0114-fqs0401200

Abstract Background Reactive oxygen species (ROS) are unavoidable by-products of oxygenic photosynthesis, causing progressive oxidative damage and ultimately cell death. Despite their destructive activity they are also signalling molecules, priming the acclimatory response to stress stimuli. Results To investigate this role further, we exposed wild type Arabidopsis thaliana plants and the double mutant npq1lut2 to excess light. The mutant does not produce the xanthophylls lutein and zeaxanthin, whose key roles include ROS scavenging and prevention of ROS synthesis. Biochemical analysis revealed that singlet oxygen (1O2) accumulated to higher levels in the mutant while other ROS were unaffected, allowing to define the transcriptomic signature of the acclimatory response mediated by 1O2 which is enhanced by the lack of these xanthophylls species. The group of genes differentially regulated in npq1lut2 is enriched in sequences encoding chloroplast proteins involved in cell protection against the damaging effect of ROS. Among the early fine-tuned components, are proteins involved in tetrapyrrole biosynthesis, chlorophyll catabolism, protein import, folding and turnover, synthesis and membrane insertion of photosynthetic subunits. Up to now, the flu mutant was the only biological system adopted to define the regulation of gene expression by 1O2. In this work, we propose the use of mutants accumulating 1O2 by mechanisms different from those activated in flu to better identify ROS signalling. Conclusions We propose that the lack of zeaxanthin and lutein leads to 1O2 accumulation and this represents a signalling pathway in the early stages of stress acclimation, beside the response to ADP/ATP ratio and to the redox state of both plastoquinone pool. Chloroplasts respond to 1O2 accumulation by undergoing a significant change in composition and function towards a fast acclimatory response. The physiological implications of this signalling specificity are discussed.

Abstract Background The production of microbial lipids has attracted considerable interest during the past decade since they can be successfully used to produce biodiesel by catalyzed transesterification with short chain alcohols. Certain yeast species, including several psychrophilic isolates, are oleaginous and accumulate lipids from 20 to 70% of biomass under appropriate cultivation conditions. Among them, Rhodotorula glacialis is a psychrophilic basidiomycetous species capable to accumulate intracellular lipids. Results Rhodotorula glacialis DBVPG 4785 is an oleaginous psychrophilic yeast isolated from a glacial environment. Despite its origin, the strain abundantly grew and accumulated lipids between -3 to 20°C. The temperature did not influence the yield coefficients of both biomass and lipids production, but had positive effect on the growth rate and thus on volumetric productivity of lipid. In glucose-based media, cellular multiplication occurred first, while the lipogenic phase followed whenever the culture was limited by a nutrient other than glucose. The extent of the carbon excess had positive effects on triacylglycerols production, that was maximum with 120 g L-1 glucose, in terms of lipid concentration (19 g L-1), lipid/biomass (68%) and lipid/glucose yields (16%). Both glucose concentration and growth temperature influenced the composition of fatty acids, whose unsaturation degree decreased when the temperature or glucose excess increased. Conclusions This study is the first proposed biotechnological application for Rhodotorula glacialis species, whose oleaginous biomass accumulates high amounts of lipids within a wide range of temperatures through appropriate cultivation C:N ratio. Although R. glacialis DBVPG 4785 is a cold adapted yeast, lipid production occurs over a broad range of temperatures and it can be considered an interesting microorganism for the production of single cell oils.

Abstract Background Archaeosomes (ARC), vesicles prepared from total polar lipids (TPL) extracted from selected genera and species from the Archaea domain, elicit both antibody and cell-mediated immunity to the entrapped antigen, as well as efficient cross priming of exogenous antigens, evoking a profound memory response. Screening for unexplored Archaea genus as new sources of adjuvancy, here we report the presence of two new Halorubrum tebenquichense strains isolated from grey crystals (GC) and black mood (BM) strata from a littoral Argentinean Patagonia salt flat. Cytotoxicity, intracellular transit and immune response induced by two subcutaneous (sc) administrations (days 0 and 21) with BSA entrapped in ARC made of TPL either form BM (ARC-BM) and from GC (ARC-GC) at 2% w/w (BSA/lipids), to C3H/HeN mice (25 μg BSA, 1.3 mg of archaeal lipids per mouse) and boosted on day 180 with 25 μg of bare BSA, were determined. Results DNA G+C content (59.5 and 61.7% mol BM and GC, respectively), 16S rDNA sequentiation, DNA-DNA hybridization, arbitrarily primed fingerprint assay and biochemical data confirmed that BM and GC isolates were two non-previously described strains of H. tebenquichense. Both multilamellar ARC mean size were 564 ± 22 nm, with -50 mV zeta-potential, and were not cytotoxic on Vero cells up to 1 mg/ml and up to 0.1 mg/ml of lipids on J-774 macrophages (XTT method). ARC inner aqueous content remained inside the phago-lysosomal system of J-774 cells beyond the first incubation hour at 37°C, as revealed by pyranine loaded in ARC. Upon subcutaneous immunization of C3H/HeN mice, BSA entrapped in ARC-BM or ARC-GC elicited a strong and sustained primary antibody response, as well as improved specific humoral immunity after boosting with the bare antigen. Both IgG1 and IgG2a enhanced antibody titers could be demonstrated in long-term (200 days) recall suggesting induction of a mixed Th1/Th2 response. Conclusion We herein report the finding of new H. tebenquichense non alkaliphilic strains in Argentinean Patagonia together with the adjuvant properties of ARC after sc administration in mice. Our results indicate that archaeosomes prepared with TPL from these two strains could be successfully used as vaccine delivery vehicles.

Motivation: Since early 2020, the coronavirus disease 2019 (COVID-19) pandemic has confronted the biomedical community with an unprecedented challenge. The rapid spread of COVID-19 and ease of transmission seen worldwide is due to increased population flow and international trade. Front-line medical care, treatment research and vaccine development also require rapid and informative interpretation of the literature and COVID-19 data produced around the world, with 177 500 papers published between January 2020 and November 2021, i.e. almost 8500 papers per month. To extract knowledge and enable interoperability across resources, we developed the COVID-19 Vocabulary (COVoc), an application ontology related to the research on this pandemic. The main objective of COVoc development was to enable seamless navigation from biomedical literature to core databases and tools of ELIXIR, a European-wide intergovernmental organization for life sciences., Results: This collaborative work provided data integration into SIB Literature services, an application ontology (COVoc) and a triage service named COVTriage and based on annotation processing to search for COVID-related information across pre-defined aspects with daily updates. Thanks to its interoperability potential, COVoc lends itself to wider applications, hopefully through further connections with other novel COVID-19 ontologies as has been established with Coronavirus Infectious Disease Ontology., Availability and Implementation: The data at https://github.com/EBISPOT/covoc and the service at https://candy.hesge.ch/COVTriage., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The current COVID-19 pandemic and the previous SARS/MERS outbreaks of 2003 and 2012 have resulted in a series of major global public health crises. We argue that in the interest of developing effective and safe vaccines and drugs and to better understand coronaviruses and associated disease mechenisms it is necessary to integrate the large and exponentially growing body of heterogeneous coronavirus data. Ontologies play an important role in standard-based knowledge and data representation, integration, sharing, and analysis. Accordingly, we initiated the development of the community-based Coronavirus Infectious Disease Ontology (CIDO) in early 2020., Results: As an Open Biomedical Ontology (OBO) library ontology, CIDO is open source and interoperable with other existing OBO ontologies. CIDO is aligned with the Basic Formal Ontology and Viral Infectious Disease Ontology. CIDO has imported terms from over 30 OBO ontologies. For example, CIDO imports all SARS-CoV-2 protein terms from the Protein Ontology, COVID-19-related phenotype terms from the Human Phenotype Ontology, and over 100 COVID-19 terms for vaccines (both authorized and in clinical trial) from the Vaccine Ontology. CIDO systematically represents variants of SARS-CoV-2 viruses and over 300 amino acid substitutions therein, along with over 300 diagnostic kits and methods. CIDO also describes hundreds of host-coronavirus protein-protein interactions (PPIs) and the drugs that target proteins in these PPIs. CIDO has been used to model COVID-19 related phenomena in areas such as epidemiology. The scope of CIDO was evaluated by visual analysis supported by a summarization network method. CIDO has been used in various applications such as term standardization, inference, natural language processing (NLP) and clinical data integration. We have applied the amino acid variant knowledge present in CIDO to analyze differences between SARS-CoV-2 Delta and Omicron variants. CIDO's integrative host-coronavirus PPIs and drug-target knowledge has also been used to support drug repurposing for COVID-19 treatment., Conclusion: CIDO represents entities and relations in the domain of coronavirus diseases with a special focus on COVID-19. It supports shared knowledge representation, data and metadata standardization and integration, and has been used in a range of applications., (© 2022. The Author(s).)

Ontologies have emerged to become critical to support data and knowledge representation, standardization, integration, and analysis. The SARS-CoV-2 pandemic led to the rapid proliferation of COVID-19 data, as well as the development of many COVID-19 ontologies. In the interest of supporting data interoperability, we initiated a community-based effort to harmonize COVID-19 ontologies. Our effort involves the collaborative discussion among developers of seven COVID-19 related ontologies, and the merging of four ontologies. This effort demonstrates the feasibility of harmonizing these ontologies in an interoperable framework to support integrative representation and analysis of COVID-19 related data and knowledge.

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven't been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery and diagnostics of Mendelian diseases. Our algorithms and tools are widely used to identify animal models of human disease through phenotypic similarity, for differential diagnostics and to facilitate translational research. Launched in 2015, Monarch has grown with regards to data (new organisms, more sources, better modeling); new API and standards; ontologies (new Mondo unified disease ontology, improvements to ontologies such as HPO and uPheno); user interface (a redesigned website); and community development. Monarch data, algorithms and tools are being used and extended by resources such as GA4GH and NCATS Translator, among others, to aid mechanistic discovery and diagnostics., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer's disease (AD) research., Objective: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs)., Methods: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence., Results: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as 'gliogenesis', 'regulation of neuron projection development', or 'response to cytokine', demonstrating enhanced applicability of GO for neuroscience research., Conclusions: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments.

The analysis and interpretation of high-throughput datasets relies on access to high-quality bioinformatics resources, as well as processing pipelines and analysis tools. Gene Ontology (GO, geneontology.org) is a major resource for gene enrichment analysis. The aim of this project, funded by the Alzheimer's Research United Kingdom (ARUK) foundation and led by the University College London (UCL) biocuration team, was to enhance the GO resource by developing new neurological GO terms, and use GO terms to annotate gene products associated with dementia. Specifically, proteins and protein complexes relevant to processes involving amyloid-beta and tau have been annotated and the resulting annotations are denoted in GO databases as 'ARUK-UCL'. Biological knowledge presented in the scientific literature was captured through the association of GO terms with dementia-relevant protein records; GO itself was revised, and new GO terms were added. This literature biocuration increased the number of Alzheimer's-relevant gene products that were being associated with neurological GO terms, such as 'amyloid-beta clearance' or 'learning or memory', as well as neuronal structures and their compartments. Of the total 2055 annotations that we contributed for the prioritised gene products, 526 have associated proteins and complexes with neurological GO terms. To ensure that these descriptive annotations could be provided for Alzheimer's-relevant gene products, over 70 new GO terms were created. Here, we describe how the improvements in ontology development and biocuration resulting from this initiative can benefit the scientific community and enhance the interpretation of dementia data.

Background: A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products., Methods and Results: In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci., Conclusions: We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects., (© 2018 The Authors.)

Huntington's disease (HD) is a fatal, dominantly inherited, neurodegenerative disorder due to a pathological expansion of the CAG repeat in the coding region of the HTT gene. In the quest for understanding the molecular basis of neurodegeneration, we have previously demonstrated that the prolyl isomerase Pin1 plays a crucial role in mediating p53-dependent apoptosis triggered by mutant huntingtin (mHtt) in vitro. To assess the effects of the lack of Pin1 in vivo, we have bred Pin1 knock-out mice with Hdh(Q111) knock-in mice, a genetically precise model of HD. We show that Pin1 genetic ablation modifies a portion of Hdh(Q111) phenotypes in a time-dependent fashion. As an early event, Pin1 activity reduces the DNA damage response (DDR). In midlife mice, by taking advantage of next-generation sequencing technology, we show that Pin1 activity modulates a portion of the alterations triggered by mHtt, extending the role of Pin1 to two additional Hdh(Q111) phenotypes: the unbalance in the "synthesis/concentration of hormones", as well as the alteration of "Wnt/β-catenin signaling". In aging animals, Pin1 significantly increases the number of mHtt-positive nuclear inclusions while it reduces gliosis. In summary, this work provides further support for a role of Pin1 in HD pathogenesis.

Background: To address the lack of standard terminology to describe extracellular RNA (exRNA) data/metadata, we have launched an inter-community effort to extend the Gene Ontology (GO) with subcellular structure concepts relevant to the exRNA domain. By extending GO in this manner, the exRNA data/metadata will be more easily annotated and queried because it will be based on a shared set of terms and relationships relevant to extracellular research., Methods: By following a consensus-building process, we have worked with several academic societies/consortia, including ERCC, ISEV, and ASEMV, to identify and approve a set of exRNA and extracellular vesicle-related terms and relationships that have been incorporated into GO. In addition, we have initiated an ongoing process of extractions of gene product annotations associated with these terms from Vesiclepedia and ExoCarta, conversion of the extracted annotations to Gene Association File (GAF) format for batch submission to GO, and curation of the submitted annotations by the GO Consortium. As a use case, we have incorporated some of the GO terms into annotations of samples from the exRNA Atlas and implemented a faceted search interface based on such annotations., Results: We have added 7 new terms and modified 9 existing terms (along with their synonyms and relationships) to GO. Additionally, 18,695 unique coding gene products (mRNAs and proteins) and 963 unique non-coding gene products (ncRNAs) which are associated with the terms: "extracellular vesicle", "extracellular exosome", "apoptotic body", and "microvesicle" were extracted from ExoCarta and Vesiclepedia. These annotations are currently being processed for submission to GO., Conclusions: As an inter-community effort, we have made a substantial update to GO in the exRNA context. We have also demonstrated the utility of some of the new GO terms for sample annotation and metadata search.

Life sciences are yielding huge data sets that underpin scientific discoveries fundamental to improvement in human health, agriculture and the environment. In support of these discoveries, a plethora of databases and tools are deployed, in technically complex and diverse implementations, across a spectrum of scientific disciplines. The corpus of documentation of these resources is fragmented across the Web, with much redundancy, and has lacked a common standard of information. The outcome is that scientists must often struggle to find, understand, compare and use the best resources for the task at hand.Here we present a community-driven curation effort, supported by ELIXIR-the European infrastructure for biological information-that aspires to a comprehensive and consistent registry of information about bioinformatics resources. The sustainable upkeep of this Tools and Data Services Registry is assured by a curation effort driven by and tailored to local needs, and shared amongst a network of engaged partners.As of November 2015, the registry includes 1785 resources, with depositions from 126 individual registrations including 52 institutional providers and 74 individuals. With community support, the registry can become a standard for dissemination of information about bioinformatics resources: we welcome everyone to join us in this common endeavour. The registry is freely available at https://bio.tools., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD., Methods: Changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set")., Results: Gene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR., Conclusions: Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.

Background: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders., Results: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database., Conclusions: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained through genome wide association studies, next generation sequencing, proteomic and transcriptomic datasets.

Background: Biological ontologies are continually growing and improving from requests for new classes (terms) by biocurators. These ontology requests can frequently create bottlenecks in the biocuration process, as ontology developers struggle to keep up, while manually processing these requests and create classes., Results: TermGenie allows biocurators to generate new classes based on formally specified design patterns or templates. The system is web-based and can be accessed by any authorized curator through a web browser. Automated rules and reasoning engines are used to ensure validity, uniqueness and relationship to pre-existing classes. In the last 4 years the Gene Ontology TermGenie generated 4715 new classes, about 51.4% of all new classes created. The immediate generation of permanent identifiers proved not to be an issue with only 70 (1.4%) obsoleted classes., Conclusion: TermGenie is a web-based class-generation system that complements traditional ontology development tools. All classes added through pre-defined templates are guaranteed to have OWL equivalence axioms that are used for automatic classification and in some cases inter-ontology linkage. At the same time, the system is simple and intuitive and can be used by most biocurators without extensive training.

Background: The mesencephalic dopaminergic (mDA) cell system is composed of two major groups of projecting cells in the Substantia Nigra (SN) (A9 neurons) and the Ventral Tegmental Area (VTA) (A10 cells). Selective degeneration of A9 neurons occurs in Parkinson's disease (PD) while abnormal function of A10 cells has been linked to schizophrenia, attention deficit and addiction. The molecular basis that underlies selective vulnerability of A9 and A10 neurons is presently unknown., Results: By taking advantage of transgenic labeling, laser capture microdissection coupled to nano Cap-Analysis of Gene Expression (nanoCAGE) technology on isolated A9 and A10 cells, we found that a subset of Olfactory Receptors (OR)s is expressed in mDA neurons. Gene expression analysis was integrated with the FANTOM5 Helicos CAGE sequencing datasets, showing the presence of these ORs in selected tissues and brain areas outside of the olfactory epithelium. OR expression in the mesencephalon was validated by RT-PCR and in situ hybridization. By screening 16 potential ligands on 5 mDA ORs recombinantly expressed in an heterologous in vitro system, we identified carvone enantiomers as agonists at Olfr287 and able to evoke an intracellular Ca2+ increase in solitary mDA neurons. ORs were found expressed in human SN and down-regulated in PD post mortem brains., Conclusions: Our study indicates that mDA neurons express ORs and respond to odor-like molecules providing new opportunities for pharmacological intervention in disease.