Modulation of Syndecan-1 Shedding after Hemorrhagic Shock and Resuscitation

The early use of fresh frozen plasma as a resuscitative agent after hemorrhagic shock has been associated with improved survival, but the mechanism of protection is unknown. Hemorrhagic shock causes endothelial cell dysfunction and we hypothesized that fresh frozen plasma would restore endothelial integrity and reduce syndecan-1 shedding after hemorrhagic shock. A prospective, observational study in severely injured patients in hemorrhagic shock demonstrated significantly elevated levels of syndecan-1 (554±93 ng/ml) after injury, which decreased with resuscitation (187±36 ng/ml) but was elevated compared to normal donors (27±1 ng/ml). Three pro-inflammatory cytokines, interferon-γ, fractalkine, and interleukin-1β, negatively correlated while one anti-inflammatory cytokine, IL-10, positively correlated with shed syndecan-1. These cytokines all play an important role in maintaining endothelial integrity. An in vitro model of endothelial injury then specifically examined endothelial permeability after treatment with fresh frozen plasma orlactated Ringers. Shock or endothelial injury disrupted junctional integrity and increased permeability, which was improved with fresh frozen plasma, but not lactated Ringers. Changes in endothelial cell permeability correlated with syndecan-1 shedding. These data suggest that plasma based resuscitation preserved endothelial syndecan-1 and maintained endothelial integrity, and may help to explain the protective effects of fresh frozen plasma after hemorrhagic shock

Direct Binding of pRb/E2F-2 to GATA-1 Regulates Maturation and Terminal Cell Division during Erythropoiesis

Cell differentiation is often coupled with cell cycle arrest. Here, we show that direct binding of the erythroid transcription factor GATA-1 to the retinoblastoma protein and the pRb/E2F transcription factor complex is critical for red blood cell formation

A Test of Highly Optimized Tolerance Reveals Fragile Cell-Cycle Mechanisms Are Molecular Targets in Clinical Cancer Trials

Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g., those involved in cell-cycle regulation, can be resistant to some perturbations while highly sensitive to others. The “robust yet fragile” duality of networks has been termed Highly Optimized Tolerance (HOT) and has been the basis of new lines of inquiry in computational and experimental biology. In this study, we tested the working hypothesis that cell-cycle control architectures obey the HOT paradigm. Three cell-cycle models were analyzed using monte-carlo sensitivity analysis. Overall state sensitivity coefficients, which quantify the robustness or fragility of a given mechanism, were calculated using a monte-carlo strategy with three different numerical techniques along with multiple parameter perturbation strategies to control for possible numerical and sampling artifacts. Approximately 65% of the mechanisms in the G1/S restriction point were responsible for 95% of the sensitivity, conversely, the G2-DNA damage checkpoint showed a much stronger dependence on a few mechanisms; ∼32% or 13 of 40 mechanisms accounted for 95% of the sensitivity. Our analysis predicted that CDC25 and cyclin E mechanisms were strongly implicated in G1/S malfunctions, while fragility in the G2/M checkpoint was predicted to be associated with the regulation of the cyclin B-CDK1 complex. Analysis of a third model containing both G1/S and G2/M checkpoint logic, predicted in addition to mechanisms already mentioned, that translation and programmed proteolysis were also key fragile subsystems. Comparison of the predicted fragile mechanisms with literature and current preclinical and clinical trials suggested a strong correlation between efficacy and fragility. Thus, when taken together, these results support the working hypothesis that cell-cycle control architectures are HOT networks and establish the mathematical estimation and subsequent therapeutic exploitation of fragile mechanisms as a novel strategy for anti-cancer lead generation

The elements of human cyclin D1 promoter and regulation involved

Cyclin D1 is a cell cycle machine, a sensor of extracellular signals and plays an important role in G1-S phase progression. The human cyclin D1 promoter contains multiple transcription factor binding sites such as AP-1, NF-қB, E2F, Oct-1, and so on. The extracellular signals functions through the signal transduction pathways converging at the binding sites to active or inhibit the promoter activity and regulate the cell cycle progression. Different signal transduction pathways regulate the promoter at different time to get the correct cell cycle switch. Disorder regulation or special extracellular stimuli can result in cell cycle out of control through the promoter activity regulation. Epigenetic modifications such as DNA methylation and histone acetylation may involved in cyclin D1 transcriptional regulation

Using persona as lenses for a reference model

This paper investigates the value of persona in relation to a conceptual product: the ENVRI reference model designed for environmental research infrastructures. Three personas have been created to understand the use of the model and the challenges faced when applying it. Personas helped identify the level of support required by different users, prioritise the audience to address first, and revealed what aspects of the model are important to different audiences. We have made significant progress in understanding how to improve communication about the model to each persona

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

The role of cell location and spatial gradients in the evolutionary dynamics of colon and intestinal crypts

BACKGROUND: Colon and intestinal crypts serve as an important model system for adult stem cell proliferation and differentiation. We develop a spatial stochastic model to study the rate of somatic evolution in a normal crypt, focusing on the production of two-hit mutants that inactivate a tumor suppressor gene. We investigate the effect of cell division pattern along the crypt on mutant production, assuming that the division rate of each cell depends on its location. RESULTS: We find that higher probability of division at the bottom of the crypt, where the stem cells are located, leads to a higher rate of double-hit mutant production. The optimal case for delaying mutations occurs when most of the cell divisions happen at the top of the crypt. We further consider an optimization problem where the “evolutionary” penalty for double-hit mutant generation is complemented with a “functional” penalty that assures that fully differentiated cells at the top of the crypt cannot divide. CONCLUSION: The trade-off between the two types of objectives leads to the selection of an intermediate division pattern, where the cells in the middle of the crypt divide with the highest rate. This matches the pattern of cell divisions obtained experimentally in murine crypts. REVIEWERS: This article was reviewed by David Axelrod (nominated by an Editorial Board member, Marek Kimmel), Yang Kuang and Anna Marciniak-Czochra. For the full reviews, please go to the Reviewers’ comments section. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13062-016-0141-6) contains supplementary material, which is available to authorized users

Dynamika i trwałość przeciwciał w włośnicy

The time of antibody appearance in 6 different serological tests and the dynamic pattern of titre were observed for 3 years and 8 month in a group of 12 experimentally infected rabbits. A similar follow-up as much for more than 8 months in a group of 13 cases with clinical and in 10 cases with subclinical trichinellosis (suspected infection). The time at which the first positive reaction appeared depended on the intensity of infection, individual properties and the test used. This appeared mostly at the end of the 3rd postinfection week, sometimes earlier but more often later. The increase of antibody titre was usually gradual reaching its peak at various periods, mostly by the 3rd month. There were interesting differences in various tests in rabbits. Antibodies have been detected in rabbits for at least 3 years and 8 month, in a group of clinical cases for 8 and half months. To prove the persistence of antibodies in man, 3 groups of patients who had had trichinellosis 7 years (19 cases), 9 years (21 cases) and 19 years (19 cases) previously were examined by various tests. Antibodies were detected even in the last group, though at lower titre and only by more sensitive tests. The persistence or rather the production of antibodies during the prolonged postinfection period is discussed against the background of chronic trichinellosis. On the basis of almost 20 years' experience and the present investigations, an evaluation of various immunological diagnostic tests in trichinellosis is given. The flocculation test with bentonite is referred to as the most simple, sensitive and specific one. The indirect fluorescent antibody test is also efficient, but more difficult to perform. The complement fixation test is less sensitive and has been found to fail many cases, probably under the inhibiting effect of drugs being used. As in the initial phase of trichinellosis positive results are not obtained simultaneously by all tests and are not predictable in individual cases, the concomitant use of several tests is recommended.Za pomocą 6 odczynów serologicznych badano czas pojawiania się przeciwciał i dynamikę zmian w ciągu 3 lat i 8 miesięcy w grupie 12 królików zarażonych doświadczalnie. Podobne badania prowadzono przez więcej niż 8 miesięcy w grupie 13 przypadków włośnicy klinicznej i 10 przypadków z włośnicą podkliniczną (podejrzanych o zarażenie). Czas pojawiania się pierwszych odczynów dodatnich zależy od intensywności zarażenia, właściwości osobniczych i stosowanego odczynu. Przeciwciała stwierdzano na ogół pod koniec 3 tygodnia po zarażeniu, czasem wcześniej, częściej jednak później. Wzrost miana przeciwciał był zwykle stopniowy, osiągając szczyt w różnych okresach, przeważnie w 3 mies. po zarażeniu. Wystąpiły tu u królików interesujące różnice między poszczególnymi odczynami. Przeciwciała wykrywano u królików przez co najmniej 3 lata i 8 mies. (najdłuższy okres badania), w grupie zaś przypadków klinicznych przez co najmniej 8 i pół miesiąca. Dla stwierdzenia trwałości przeciwciał u człowieka zbadano różnymi próbami 3 grupy osób, które przebyły włośnicę kliniczną przed 7 laty (19 osób), 9 laty (21 osób) i 19 laty (19 osób). Nawet w ostatniej grupie wykryto jeszcze przeciwciała u niektórych osób, choć z niskim mianem i tylko przy pomocy bardziej czułych prób. Dyskutuje się w świetle włośnicy przewlekłej trwałość lub raczej wytwarzanie przeciwciał w czasie tak długiego okresu po zarażeniu. W oparciu o blisko 20-letnie doświadczenia autorów i obecne badania podano ogólną ocenę różnych odczynów immunologicznych we włośnicy. Odczyn aglutynacji z bentonitem jest spośród najprostszych najbardziej czuły i swoisty. Odczyn fluorescencyjny pośredni jest nie mniej dobry, ale trudniejszy do wykonania w rutynowej diagnostyce. Odczyn wiązania dopełniacza uważamy za mniej czuły od poprzednich i zawodny w niektórych przypadkach, szczególnie leczonych kortykosteroidami. Ponieważ w początkowej fazie włośnicy nic uzyskuje się wyników dodatnich równocześnie przy pomocy wszystkich prób i trudno przewidywać, która próba, w którym przypadku wypadnie wcześniej dodatnio, zaleca się stosowanie możliwie kilku prób jednocześnie