The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins: A Novel Pathway for Inflammatory Cell Recruitment

The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the β2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with β1-integrins. The RAGE–Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric β2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE–Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications

Der vaskuläre endotheliale Wachstumsfaktor VEGF hemmt die Endothelzellapoptose über Regulation von PARP

Der vaskuläre endotheliale Wachstumsfaktor (VEGF) ist der stärkste Überlebensfaktor für Endothelzellen. Der anti-apoptotische Effekt von VEGF auf das Endothel ist allgemein bekannt, jedoch sind die Mechanismen, die zu der Apoptosehemmung führen, weitgehend unbekannt. Daher wurde die Hypothese untersucht, dass VEGF über die Regulation eines Caspasen-Mediators, wie Poly(ADP-ribose)-Polymerase (PARP), wirkt. In der vorliegenden Arbeit wird ein neuartiger Wirkmechanismus von VEGF über die Hochregulation des intrazellulären anti-apoptotischen Proteins PARP aufgezeigt. Endothelzellen, HUVEC sowie die Zelllinien EA.hy926 und hCMEC/D3, wurden mit VEGF in unterschiedlichen Konzentrationen (100 pg/ml - 1 µg/ml) inkubiert. VEGF induzierte in Endothelzellen dosisabhängig die Proteinexpression von PARP, wie mittels automatisierter Densitometrie von Western Blots gezeigt wurde. Die mRNA -Produktion von PARP war ebenfalls erhöht, wie in der Real-time RT-PCR demonstriert. VEGF induzierte auch eine erhöhte PARP-Aktivität, wie mithilfe des colorimetrischen PARP-Aktivitätsassays gezeigt. Wiederholte Zugabe von VEGF zu Endothelzellen alle 48 Stunden über eine Inkubationszeit von 6 Tagen führte zu einem stärkeren Anstieg der PARP- Protein- und mRNA-Produktion. Durch durchflusszytometrische Annexin V-FITC / Propidium-Jodid-Messung konnte gezeigt werden, dass VEGF in den untersuchten Konzentrationen die Sensitivität der Endothelzellen für Apoptose, induziert durch Adhäsions-Hemmung mithilfe des αv-Integrinantagonisten cRGDfV, um 60 % bei einmaliger Applikation und um 90 % bei dreimaliger Applikation von VEGF reduzieren konnte, im Vergleich zu Zellen, die nicht mit VEGF vorbehandelt worden waren. Die Induktion von PARP durch VEGF wurde auf der Ebene der Transkription reguliert, gezeigt durch Co-Inkubation mit Actinomycin D, ein potenter Inhibitor der Transkription. Inkubation mit Cycloheximid, einem Translationsinhibitor, hatte keinen Einfluss auf das PARP-Protein. Demzufolge erhöht VEGF die Genexpression von PARP. bFGF oder TGFβ hatten keinen Einfluss auf die PARP-Produktion, der beobachtete Effekt war daher VEGF-spezifisch. Der VEGF-Rezeptor-2 (VEGFR-2) wurde mittels Immunfluoreszenz auf Endothelzellen nachgewiesen. Ebenfalls konnte der VEGFR-2 Ko-Rezeptor Neuropilin-1 (NP-1) auf Endothelzellen nachgewiesen werden. In die Signaltransduktion von VEGF war VEGFR-2 involviert, wie Ko-Inkubationen mit dem VEGFR-2 Inhibitor SU5416 zeigen konnten. Downstream des Rezeptors wiesen wir die Beteiligung von SAPK/JNK und Akt nach. Um den direkten Zusammenhang zwischen VEGF und der Hochregulation von PARP nachzuweisen, wurden Endothelzellen mit PARP-siRNA behandelt und mit VEGF 100 pg/ml – 1 ng/ml präinkubiert. Transfektion mit PARP-siRNA führt zu einer fast vollständigen Reduktion der Expression von PARP-Protein in Endothelzellen. Mit PARP-siRNA transfizierte Endothelzellen zeigten keine Reduktion der im Durchflusszytometer gemessene Apoptoserate durch Präinkubation mit VEGF im Vergleich zu nicht-transfizierten Zellen, der PARP mRNA-Knockdown konnte also die Apoptosehemmung durch VEGF aufheben. Die vorliegenden Ergebnisse zeigen, dass VEGF einen Hauptteil seines anti-apoptotischen Effekts auf Endothelzellen über die Regulation der PARP-Expression ausübt. Die Hochregulierung des intrazellulären Proteins PARP durch VEGF könnte einen auto-protektiven Mechanismus der Gefäße zur Neutralisation der pro-apoptotischen Caspasen-Aktivität darstellen, um die endotheliale Empfindlichkeit gegenüber apoptotischen Stimuli zu reduzieren. Dieser Mechanismus könnte Einfluss haben auf die Angiogenese und die Entstehung von Arteriosklerose. Das Verständnis der schützenden Wirkungen von VEGF auf Endothelzellen ist der Schlüssel für die Entwicklung neuer Therapien der Arteriosklerose und anderer mit VEGF assoziierter Erkrankungen

ПОЯСНЮВАЛЬНА ЗАПИСКА кваліфікаційної роботи бакалавра студента Козаченко Артема Олександровича групи САіт-15-2 напряму підготовки 124 Системний аналіз

Економічна ефективність: очікується позитивною завдяки аналізу web-орієнтованої системи та розробці програмного забезпечення, які дозволяють покращити відвідуваність сайту користувачами, впроваджувати монетизацію за допомогою реклами тим самим збільшуючи дохід власника. Практична значимість результатів: полягає в тому, що їх можна успішно використовувати в реальному менеджменті складних сучасних систем. Пропозиціі щодо розвитку: передбачається розглянути питання використання запропонованої концепції функціонального опису систем при проектуванні нових систем. В інформаційно-аналітичному розділі розглядаються питання опису функціональної структури web-орієнтованих інформаційних систем. Пропонується метод опису функціональних структур і метод аналізу функціональної достатньості спроектованих систем. Обговорюються практична реалізація для менеджменту систем. У спеціальному розділі описуються етапи створення мобільного додатку для сайту з метою розширення аудиторії та покращення функціональної забезпеченості системи та розроблений прогноз користувачів web-орієнтованої інформаційної системи для подальшого аналізу достатньості системи.Об’єкт дослідження: функціональна структура web-орієнтованих інформаційних систем.Предмет дослідження: методологічні основи побудови класифікацій web-орієнтованих систем та методи опису функціональних структур і аналізу функціональної достатності спроектованих систем.Мета роботи: розгляд питання опису функціональної структури проектованої інформаційної системи та покращення функціональної забезпеченості системи.Методи дослідження: метод аналізу функціональної забезпеченості інформаційної системи, методи прогнозу, мова програмування Java

Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis

Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor-specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the αV-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt. In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to prevent cellular damage in cerebrovascular disease

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world. FundingBill & Melinda Gates Foundation

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.</p

Elliptic anisotropy measurement of the f0_0(980) hadron in proton-lead collisions and evidence for its quark-antiquark composition

International audienceDespite the f$_0$(980) hadron having been discovered half a century ago, the question about its quark content has not been settled: it might be an ordinary quark-antiquark ($\mathrm{q\bar{q}}$) meson, a tetraquark ($\mathrm{q\bar{q}q\bar{q}}$) exotic state, a kaon-antikaon ($\mathrm{K\bar{K}}$) molecule, or a quark-antiquark-gluon ($\mathrm{q\bar{q}g}$) hybrid. This paper reports strong evidence that the f$_0$(980) state is an ordinary $\mathrm{q\bar{q}}$ meson, inferred from the scaling of elliptic anisotropies ($v_2$) with the number of constituent quarks ($n_\mathrm{q}$), as empirically established using conventional hadrons in relativistic heavy ion collisions. The f$_0$(980) state is reconstructed via its dominant decay channel f$_0$(980) $\to$$\pi^+\pi^-$, in proton-lead collisions recorded by the CMS experiment at the LHC, and its $v_2$ is measured as a function of transverse momentum ($p_\mathrm{T}$). It is found that the $n_q$ = 2 ($\mathrm{q\bar{q}}$ state) hypothesis is favored over $n_q$ = 4 ($\mathrm{q\bar{q}q\bar{q}}$ or $\mathrm{K\bar{K}}$ states) by 7.7, 6.3, or 3.1 standard deviations in the $p_\mathrm{T}$$\lt$ 10, 8, or 6 GeV/$c$ ranges, respectively, and over $n_\mathrm{q}$ = 3 ($\mathrm{q\bar{q}g}$ hybrid state) by 3.5 standard deviations in the $p_\mathrm{T}$$\lt$ 8 GeV/$c$ range. This result represents the first determination of the quark content of the f$_0$(980) state, made possible by using a novel approach, and paves the way for similar studies of other exotic hadron candidates