Functional and transcriptional differences in monocytes from children with obesity compared to children of healthy weight

Background and aim Cardiometabolic risk accrues across the entire life course and childhood is a key epoch for effective prevention. Obesity in childhood is the most prevalent modifiable risk factor for later cardiovascular disease (CVD). Inflammatory biomarkers and innate immune capacity are increased in adults with obesity, but childhood data are scarce. We aimed to investigate (i) innate immune cell activation in children with and without obesity; and (ii) whether weight loss impacts the innate immune inflammatory phenotype. Methods The innate immune phenotype of Peripheral Blood Mononuclear Cells (PBMCs) from 31 children with obesity (BMI z-score>2.5) and 22 children of healthy weight (−1.5≤BMIz≤1.5, sex, age and pubertal stage matched) was characterized by high dimensional flow cytometry, ex vivo stimulation assays with subsequent 27-plex cytokine measurements, and transcriptome analysis using RNA sequencing (Figure 1). Children with obesity participated to the Royal Children's Hospital Weight Management Service (median 5 years) and at follow-up, PBMCs were obtained again as well as anthropometric data and subclinical cardiovascular phenotypes. Results Flow cytometric analysis showed marked differences in cell composition between children with obesity and children of healthy weight. Specifically, children with obesity have significant changes in monocyte subsets and an increased expression of monocyte activation markers. Upon stimulation, monocytes of children with obesity show an increased cytokine production capacity. Finally, transcriptomic analysis shows significant differences between monocytes from obese children and healthy controls. Effects of weight loss on these immune parameters and correlations with preclinical CVD phenotypes are currently being analysed. Conclusions Monocytes from children with obesity have a pro-inflammatory phenotype compared to children of normal weight. Heightened inflammation may contribute to increased CVD risk later in life and may offer opportunities for early intervention. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Dutch Scientific Organisation (NWO) - Rubicon grant to S.B. Dutch Heart Foundation - CVON IN CONTROL II to N.P.R. and D.B. Figure 1. Schematical overview of study

Paying lip service to publication ethics: scientific publishing practices and the Foundation for a Smoke-Free World

Litigation forced the dissolution of three major tobacco industry-funded organisations because of their egregious role in spreading scientific misinformation. Yet in 2017, a new scientific organisation—the Foundation for a Smoke-Free World (FSFW)—was launched, funded entirely by tobacco corporation Philip Morris International (PMI). Experts fear FSFW similarly serves to benefit its funder’s scientific and political agenda. We present three case studies of FSFW’s publishing practices to explore: whether FSFW and its affiliates are acting with scientific integrity in their attempts to publish research; how conflicts of interest (COI) are governed in the journals FSFW targets; whether scientific publishing needs to be better protected from the tobacco industry in light of this, and if so, how. FSFW and its grantees have resorted to repeated obfuscation when publishing their science. FSFW staff have failed to act transparently and arguably have sought control over editorial processes (at times facilitated by PR firm, Ruder Finn). FSFW-funded organisations (including its Italian ‘Centre of Excellence’) and researchers affiliated with FSFW (including those working as editors and peer-reviewers) have failed to disclose their links to FSFW and PMI. While journals also failed to apply their COI policies, including on tobacco industry-funded research, the findings highlight that such policies are almost entirely dependent on researchers fully declaring all potential COIs. The paper explores ways to address these problems, including via standardised reporting of COI and funding in journals; journal policies prohibiting publication of tobacco industry-funded science; development of an author-centric database of financial interests; and legally mandated tobacco industry financial contributions to fund science on new tobacco and nicotine products.

Structure of Personnel in Scientific Organisations of the Ministry of Science and Higher Education of the Russian Federation for Individual Regions: Analysis of Primary Statistical Information

Introduction. The subject of this work is the number, composition and structure of personnel of research organisations subordinate to the Ministry of Science and Higher Education of the Russian Federation, located in regions that differ in terms of research and development conditions. Such information can be useful in identifying stable characteristics of the personnel model of a scientific organisation for the formation of a system of restrictions that will allow in the future to develop an optimal personnel model of a scientific organisation for a given target criterion. Methods. To achieve this goal, theoretical (analysis) and empirical (structuring the available data, generalization, classification, comparison) research methods were used. The empirical base of the research was information on the number and composition of personnel of scientific organisations subordinate to the Ministry of Science and Higher Education of the Russian Federation, presented in the database of the statistical observation form, Form ZP-Science. Results and Discussion A review of the number, composition and structure of personnel of research organisations is carried out for a sample of 278 organisations in several regions of Russia, differing not only in the number of scientific institutions represented on their territory under the jurisdiction of the Ministry of Science and Higher Education of the Russian Federation, but also in socio-economic conditions. Conclusion. The analysis made it possible to identify the characteristics of the personnel model of a scientific organisation subordinate to the Ministry of Education and Science of the Russian Federation, which is resistant to differences in the regional environment.

ECOLOGICAL AND ECONOMIC JUSTIFICATION OF THE INVESTMENTS’ EFFICIENCY IN THE INTEGRATED DEVELOPMENT OF TERRITORIES

"Intensive human economic activity has led to decrese in the natural resource potential of territories and qualitative changes in the natural environment surrounding a person: a violation of the spatial and functional structure of natural systems, a decrease in the biological diversity of flora and fauna, a deterioration in the quality of water and land resources, a decrease in the ecological and economic sustainability of technical and natural systems and the quality of human life. Ensuring the sustainable functioning and development of territories is possible due to the complex arrangement of the territory (scientific organisation of the territory). It is the optimisation of the land using structure that will restore disturbed ecosystems to standard values, increase biological diversity, environmental sustainability and economic efficiency of landscapes. One of the limiting factors in the implementation of this measure is the lack of an effective mechanism for assessing the effectiveness of investments in land development. All this indicates the need to develop proposals for the development of methodological approaches to assessing the environmental and economic efficiency of investments in land development, taking into account the shortcomings that we identified when analyzing existing approaches to assessing the effectiveness of investment projects of social significance. At the same time, it should be noted that ensuring sustainable development of territories is impossible with the existing nature-intensive concept of economic development. A new approach to solving this problem is needed, which should: • be based on a deep study of socio-economic and environmental problems, a retrospective analysis of the state of landscapes and a long-term forecast of the expected consequences of the impact of human activity on the state of individual components of the considered territory and the landscape as a whole; • it aims to ensure the socio-economic and environmental safety of Russia. The рurpose is to develop proposals for the development of a methodological approach to assessing the environmental and economic efficiency of investments in the integrated development of territories which are aimed at ensuring the socio-economic and environmental security of Russia."

The presence of fungal and parasitic infections in substances of human origin and their transmission via transfusions and transplantations: A protocol of two systematic reviews (Preprint)

BACKGROUND The European Union Directives stipulate mandatory tests for the presence of some infections in donors or donations of substances of human origin (SoHO). In some circumstances, other pathogens including fungi and parasites may also pose a threat to the microbial safety of SoHO. OBJECTIVE The aim of the two systematic reviews is to identify, collect and evaluate scientific evidence for the presence of a) fungal and b) parasitic infections in donors and donations of SoHO, and their transmission via transfusion and transplantation. METHODS One algorithmic searching for fungal and one for parasitic diseases were applied in six scientific databases [PubMed; EMBASE; Web of Science; Scopus; Cochrane library (trials); CINAHL]. In addition, manual and algorithmic searches employed in 15 grey literature databases and 22 scientific organisation websites. Selection criteria for eligibility includes peer-reviewed publications and/or peer reviewed abstract publications from conference proceedings, which have examined prevalence/incidence, odds/risk ratios, risk difference of the presence of a) fungal and b) parasitic infections transmission in SoHO donor or donation and their transmission to recipients. Only studies that scrutinised donors and donated human blood, blood components, tissues, cells and organs, were considered as eligible. Data extraction from the eligible publications will be performed independently by two review team members. Data synthesis will include a qualitative description for the studies that will not provide evidence suitable for a meta-analysis and a random or fixed-effect meta-analysis model for quantitative data synthesis. RESULTS This is an ongoing study and presents a protocol of two systematic reviews to identify, collect and evaluate scientific evidence for the presence of a) fungal and b) parasitic infections in donors and donations of SoHO, and their transmission via transfusion and transplantation. CONCLUSIONS These systematic reviews will provide a basis for the development of a risk assessment of fungal and parasitic diseases transmission via SoHO. CLINICALTRIAL The systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42020160090; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=160090 CRD42020160110; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=160110

International academic mobility through the prism of soft power theory

Introduction. In the era of globalisation and digitalisation of society, the phenomenon of mobility is of particular relevance in the humanitarian discourse. Technological, socio-political and economic changes, penetrating into the sectors of education and science, contribute to internationalisation, intensification, as well as the inclusive growth of these priority areas of society. The study of academic mobility in the context of the theory of soft power will make it possible quantitatively measure and qualitatively evaluate the information and educational infrastructure as a separate educational and scientific organisation, and the country as a whole. The aim of the present research is to comprehensively consider the international academic mobility of students as a component and recourse of the country’s soft power in post-industrial realities.Methodology and research methods. The methodological framework of the research involves discursive and conceptual approaches. The following general scientific methods were used: comparative and system-structural analysis, synthesis, generalisation and comparative method. Statistical reports and data from global rating systems were analysed and processed through the method of secondary data analysis. The coefficient of rank correlation of the relationship between the number of foreign students in the countries (included in the Top 30 of soft power) and indicators of the rating of the world universities was calculated according to Spirman’s rank correlation test.Results and scientific novelty. The theories of soft power and academic mobility are synthesised on the basis of an analytical review of scientific publications by European, American, Russian and Chinese scientists. The hypothesis of the close interdependence of these concepts is confirmed. Academic mobility, including the virtual one, is shown to be an important tool for achieving geopolitical and economic goals both in the long-term and short-term perspectives. It is established that academic mobility, on the one hand, is determined from the standpoint of economic and political expediency; on the other hand, as a consequence of the globalisation, transforming the higher education system. While Western researchers emphasise the positive aspects of international law by students and scientists, the Russian scientific discourse is largely focused on the negative trends of this process. Two directions of soft power formation in the field of education are identified: training of future leaders (elite) and education of ordinary citizens. The authors revealed the vectors of the discussed type of mobility – Western-centric (Anglo-American) and the new one Asian (Eurasian), in whichChinaand the Chinese language take a special place. It was initiated to establish the SCO University Network among the representatives of member states in order to balance educational flows. The obstacles to its effectiveness are identified.Practical significance. The research findings and conclusions extend the knowledge of the possibilities and limitations of the academic mobility realisation to increase university competitiveness.

The SUMO conjugation complex self-assembles into nuclear bodies independent of SIZ1 and COP1

One sentence SummarySUMO conjugation activity causes formation of SUMO nuclear bodies, which strongly overlap with COP1 bodies thanks to a substrate-binding (VP) motif in the E3 ligase SIZ1 that acts as bridge protein.AbstractAttachment of the small ubiquitin-like modifier SUMO to substrate proteins modulates their turnover, activity or interaction partners. An unresolved question is how this SUMO conjugation activity concentrates the enzymes involved and the substrates into uncharacterized nuclear bodies (NBs). We here define the requirements for the formation of SUMO NBs and for their subsequent co-localisation with the master regulator of growth, the E3 ubiquitin ligase COP1. COP1 activity results in degradation of transcription factors, which primes the transcriptional response that underlies elongation growth induced by night-time and high ambient temperatures (skoto- and thermomorphogenesis, respectively). SUMO conjugation activity itself is sufficient to target the SUMO machinery into NBs. Co-localization of these bodies with COP1 requires besides SUMO conjugation activity, a SUMO acceptor site in COP1 and the SUMO E3 ligase SIZ1. We find that SIZ1 docks in the substrate-binding pocket of COP1 via two VP motifs - a known peptide motif of COP1 substrates. The data reveal that SIZ1 physically connects COP1 and SUMO conjugation activity in the same NBs that can also contain the blue-light receptors CRY1 and CRY2. Our findings thus suggest that sumoylation apparently coordinates COP1 activity inside these NBs; a mechanism that potentially explains how SIZ1 and SUMO both control the timing and amplitude of the high-temperature growth response. The strong co-localization of COP1 and SUMO in these NBs might also explain why many COP1 substrates are sumoylated.Funding informationThe Netherlands Scientific Organisation (ALW-VIDI grant 864.10.004 to HvdB) and the Topsector T&U program Better Plants for Demands (grant 1409-036 to HvdB), including the partnering breeding companies, supported this work; FM is financially supported by Keygene N.V. (The Netherlands).

HISTORICAL FACTORS OF THE DEVELOPMENT OF SCIENTIFIC ORGANISATION OF PRODUCTION SYSTEMS

The article presents the main factors of the industrial system of the enterprise and their development in evolution of scientific organization of production. The main principles underlying the efficient production system have been described. The comparison of the main stages of the development of the science of production organization and management has been done.

Ablation of Dicer1 in Myeloid Progenitors Leads to Neutrophil Dysplasia and Depletion of Monocytes, Macrophages, and Myeloid Dendritic Cells

Abstract 43 MicroRNAs (miRNAs) belong to a family of small non-coding RNAs that post-transcriptionally suppresses protein-coding mRNAs. DICER1 is an RNaseIII endonuclease that is critical for processing precursor hairpin sequences into mature miRNAs. Thus, cell type- and developmental stage-specific conditional deletion of Dicer1 can be used to investigate the consequences of global miRNA depletion in myeloid cell development. We crossed mice that contained floxed Dicer1 (Dicer1fl) alleles with different Cre-recombinase transgenic mice, in which CRE is expressed at different stages of myelopoiesis. In addition, we used a CRE-dependent YFP reporter system for the identification of cells that contain Dicer1 deleted alleles (Dicer1δ). Deletion of Dicer1 with VAVi-Cre transgenic mice, which is expressed in hematopoietic stem cells (HSCs), results in full depletion of hematopoiesis, indicating that Dicer1 is critical for stem cell maintenance. To investigate the role of Dicer1 in granulocyte macrophage progenitors (GMPs), we crossed CCAAT/enhancer binding protein a (C/ebpa)-Cre mice with the Dicer1 deleter strain that also harbored a conditional YFP allele. Because these mice suffered from late embryonic lethality due to pulmonal dysfunction, we performed transplantation with isolated HSCs from embryonic day 13.5 fetal livers. We observed a full deletion of Dicer1fl alleles and a near complete depletion of miRNAs in YFP+ bone marrow cells. Strikingly, C/ebpa-Cre-driven deletion of Dicer1, did not affect the number of YFP+ multi-potent progenitors (MPPs), common myeloid progenitors (CMPs) and GMPs compared to wild type (wt) Dicer1 mice. However, complete loss of Dicer1 blocked monocytic differentiation, depleted macrophages and myelo-dendritic cells, and caused myeloid dysplasia with morphological features of Pelger-Huët anomaly. In addition, decreased colony formation in response to G-CSF and GM-CSF, and a block in myelo-dendritic cell outgrowth were observed when Dicer1δ/δ progenitors were grown in vitro. Cytologic analysis of the Dicer1δ/δ colonies demonstrated a strong reduced ability to produce mature macrophages and neutrophils. Instead, we observed outgrowth of blast-like cells that exhibited an increased replating capacity, which is suggestive for an enhanced self-renewal capacity. MiRNA profiling of wt GMPs (Lin−Sca-1−c-Kit+CD34+FcgRII/III(CD16/32)High) showed expression of 104 out of a panel of 375 well-characterized miRNAs tested. To further investigate the functions of these miRNAs, we profiled the gene expression of Dicer1δ/δ and Dicer1wt/δ GMPs and compared the transcriptome to wt Dicer1 control cells. In total, Dicer1 ablation resulted in 300 significantly up-regulated and 88 down-regulated transcripts in GMPs. Transcripts with predicted miRNA binding sites for miRNAs that are expressed in GMPs tended to be derepressed in the Dicer1δ/δ cells relative to transcripts that do not have predicted miRNA binding sites (Kolmogorov-Smirnov test, p<2.2×10−16). Further, predicted targets of twenty miRNAs seeds including Let-7, miR-17, miR-142, miR-223, and miR-30 were significantly enriched in the up-regulated fraction of transcripts (Fisher exact test, FDR, p<0.05). Gene set enrichment analysis shows that differentially expressed genes are involved in cell death, cancer, and cellular growth and proliferation mainly. Further, we identified a set of Dicer1 controlled transcripts, which are exclusively expressed in self-renewing HSC such as Cav2 and Bach1, genes that are specific for the HSC/MPP stage, including HoxA9 and Hmga2, and genes that are erythroid progenitor specific, such as Nfe2l2 and Wwp1. In conclusion, Dicer1 ablation by C/ebpa-Cre does not affect the numbers of HSCs, CMPs, and GMPs but results in defective GMPs, which are unable to mature towards monocytes, macrophages, and myeloid dendritic cells, and give rise to a neutrophil dysplasia instead. These data thus uncover a Dicer1-controlled differentiation program in GMPs that is required for normal myelopoiesis. Grant: Dutch Scientific Organisation (NWO-VENI) and Dutch Cancer Society (KWF) Disclosures: No relevant conflicts of interest to declare.

̒Still Arguing Over Cost̓: Bargaining, Etiquette and the Modern Patient in Republican Beijing

In this article I have endeavoured to show how conflicting notions of consumer etiquette and patient behaviour played out during negotiations between social workers and patients at Peking Union Medical College Hospital (PUMC) in the 1930s. Organisational technologies such as quantification, record keeping, statistics, standardisation and systematisation were essential aspects of the American-style scientific medicine that PUMC aimed to introduce to China in the Republican period. Chinese patients brought assumptions of their own to the American hospital, however. Wealthy women in particular insistently bargained over the price of treatment, thereby adopting a selective approach to hospital therapies. In response, hospital social workers, who were allowed considerable flexibility about the manner of negotiating prices, adapted payment customs to satisfy this class of patients. At the same time, social workers wielded their control over resources with an eye toward disciplining patients in various ways. They investigated patients' financial circumstances, gathering evidence in order to compel more truthful self-disclosure, or a posture of deference toward scientific and institutional authority. In Republican Beijing a 'modem' Chinese patient role thus evolved through a process of mutual, if asymmetrical, negotiation. Themes that become visible in the process of negotiating payment are suggestive of ways PUMC, as a model of administrative modernity and scientific organisation, was both linked to—and diverged from—consumer practices and concepts of distributive justice rooted in a distant society.