The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

© 2016 Chorny et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell-independent and T cell-dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.This study was supported by European Advanced grant ERC-2011-ADG-20110310, Ministerio de Ciencia e Innovación grant SAF2011-25241, and Marie Curie reintegration grant PIRG-08-GA-2010-276928 to A. Cerutti; Sara Borrell post-doctoral fellowships to A. Chorny; and US National Institutes of Health grants R01 AI57653, U01 AI95613, P01 AI61093, and U19 096187 to A. Cerutti. C. Cunha and A. Carvalho were funded by grants from Fundação para a Ciência e Tecnologia, co-funded by Programa Operacional Regional do Norte (ON.2—O Novo Norte)., and from the Quadro de Referência Estratégico Nacional (SFRH/BPD/96176/2013 to C. Cunha and grant IF/00735/2014 to A. Carvalho) through the Fundo Europeu de Desenvolvimento Regional and Projeto Estratégico (LA 26 – 2013–2014; PEst-C/SAU/LA0026/2013). The financial support of the European Commission (FP7-HEALTH-2011-ADITEC-No.280873 and ERC-PHII-669415) to A. Mantovani is gratefully acknowledged.info:eu-repo/semantics/publishedVersio

Predicting In Vivo Efficacy of Potential Restenosis Therapies by Cell Culture Studies: Species-Dependent Susceptibility of Vascular Smooth Muscle Cells

Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat≥rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum

Co-encapsulation of human serum albumin and superparamagnetic iron oxide in PLGA nanoparticles: Part I. Effect of process variables on the mean size

PLGA (poly d,l-lactic-co-glycolic acid) nanoparticles (NPs) encapsulating magnetite nanoparticles (MNPs) along with a model drug human serum albumin (HSA) were prepared by double emulsion solvent evaporation method. This Part I will focus on size and size distribution of prepared NPs, whereas encapsulation efficiency will be discussed in Part II. It was found that mean hydrodynamic particle size was influenced by five important process variables. To explore their effects, a five-factorial, three-level experimental design and statistical analysis were carried out using STATISTICA® software. Effect of process variables on the mean size of nanoparticles was investigated and finally conditions to minimize size of NPs were proposed. GAMS™/MINOS software was used for optimization. The mean hydrodynamic size of nanoparticles ranged from 115 to 329 nm depending on the process conditions. Smallest possible mean particle size can be achieved by using low polymer concentration and high dispersion energy (enough sonication time) along with small aqueous/organic volume ratio

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation–related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell–independent and T cell–dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.European Advanced grant ERC-2011-ADG-20110310, Ministerio de Ciencia e Innovación grant SAF2011-25241, and Marie Curie reintegra -tion grant PIRG-08-GA-2010-276928 to A. Cerutti; Sara Borrell post-doctoral fellow -ships to A. Chorny; and US National Institutes of Health grants R01 AI57653, U01 AI95613, P01 AI61093, and U19 096187 to A. Cerutti. C. Cunha and A. Carvalho were funded by grants from Fundação para a Ciência e Tecnologia, co-funded by Programa Operacional Regional do Norte (ON.2—O Novo Norte)., and from the Quadro de Referência Estratégico Nacional (SFRH/BPD/96176/2013 to C. Cunha and grant IF/00735/2014 to A. Carvalho) through the Fundo Europeu de Desenvolvimento Regional and Projeto Estratégico (LA 26 – 2013–2014; PEst-C/SAU/LA0026/2013

A Concerted Kinase Interplay Identifies PPARγ as a Molecular Target of Ghrelin Signaling in Macrophages

The peroxisome proliferator-activator receptor PPARγ plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARγ. Although the interplay between CD36 and PPARγ in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARγ remains unknown. Here, we demonstrate that ghrelin triggers PPARγ activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRα and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARγ phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARγ Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARγ activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARγ response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Gαq-dependent manner, resulting in Akt recruitment to PPARγ, enhanced PPARγ phosphorylation and activation independently of Ser-84, and increased expression of LXRα and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Gαq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARγ to ghrelin in macrophages

Экспериментальное исследование теплогидравлических характеристик оребренных плоских труб аппарата воздушного охлаждения масла

Air cooling devices are heat exchange units that are widely used in practice. However, they have a number of disadvantages due to the low value of the heat transfer coefficient from the air and the high resistance of finned tube bundles, which leads to large dimensions and the metal content of the device itself, to the need to develop a high power ventilator drive, but also to the need to demonstrate reduced energy efficiency. The objective of the present work is to determine optimal geometric sizes of finned flat heat exchange tubes manufactured by the techniques of extrusion and deforming cutting that reduce the weight and size characteristics of the heat exchange section of air cooling devices. The experimental studies of seven various samples of heat exchange sections, being different in fin pitch and height, tube section width, flat tube height and a number of inner channels, have determined the performance of each section with the use of the following criteria: thermal power, thermal efficiency, specific thermal heat transfer resistance, M. V. Kirpichev and V. M. Antuf’ev’s criteria. The obtained experimental data and the analysis of the passive method of enhancement in the near-wall area of the heat transfer surface finned by deforming cutting has shown that sample No 5 has maximum value of the performance criteria when the maximum height of a fin is 0.008 m and the minimum pitch of a fin is 0.0025 m over the investigated sample range. Thus, when the sizes of an oil air cooling device are maintained by using the amended heat transfer section of sample No 5, the amount of removed heat can be increased or the mass and dimensions of the device can be decreased while maintaining thermal power and, as a result, the power consumption for pumping can be decreased and the thermal-hydraulic performance of the device as a whole can be increased.Аппараты воздушного охлаждения представляют собой класс теплообменных агрегатов, широко применяемых на практике. Однако они обладают рядом недостатков, обусловленных малым значением коэффициента теплоотдачи со стороны воздуха и большим сопротивлением оребренных трубных пучков. Это приводит к большим габаритам и металлоемкости самого устройства, к необходимости развивать высокую мощность привода вентилятора, что снижает энергетическую эффективность. Цель исследований – определение оптимальных геометрических размеров оребренных плоских теплообменных труб, получаемых методами экструзии и деформирующего резания, обеспечивающих снижение массогабаритных характеристик теплообменной секции аппаратов воздушного охлаждения. На основании проведенных экспериментов с семью различными образцами теплообменных секций, отличающихся шагом и высотой ребер, шириной секции трубы, высотой плоской трубы и количеством внутренних каналов, установлена эффективность каждой секции по таким показателям, как: тепловая мощность, тепловая эффективность, удельное термическое сопротивление теплопередаче, критерии М. В. Кирпичева и В. М. Антуфьева. Полученные экспериментальные данные и анализ пассивного метода воздействия на пристенную область теплопередающей поверхности за счет оребрения методом деформирующего резания показывают, что максимальное значение критериев эффективности наблюдается у образца № 5 с наибольшей высотой (0,008 м) и минимальным шагом ребер (0,0025 м) в исследованном диапазоне. Таким образом, при сохранении геометрических размеров аппарата воздушного охлаждения масла за счет использования улучшенной секции теплообменного аппарата (образец № 5) возможно увеличение количества отводимой теплоты или уменьшение массогабаритных характеристик при сохранении тепловой мощности и, как следствие, снижение затрат мощности на прокачку и повышение теплогидравлической эффективности аппарата в целом

The Neutrophil Life Cycle.

Neutrophils are recognized as an essential part of the innate immune response, but an active debate still exists regarding the life cycle of these cells. Neutrophils first differentiate in the bone marrow through progenitor intermediaries before entering the blood, in a process that gauges the extramedullary pool size. Once believed to be directly eliminated in the marrow, liver, and spleen, neutrophils, after circulating for less than 1 day, are now known to redistribute into multiple tissues with poorly understood kinetics. In this review, we provide an update on the dynamic distribution of neutrophils across tissues in health and disease, and emphasize differences between humans and model organisms. We further highlight issues to be addressed to exploit the unique features of neutrophils in the clinic

Regulation of the polymeric immunoglobulin receptor by the classical and alternative NF-κB pathways in intestinal epithelial cells

The polymeric immunoglobulin receptor (pIgR) transports IgA antibodies across intestinal epithelial cells (IECs). Expression of pIgR is upregulated by proinflammatory signaling pathways via activation of nuclear factor-κB (NF-κB). Here, we examined the contributions of the RelA-dependent classical and RelB-dependent alternative pathways of NF-κB to pIgR regulation in the HT-29 human IEC line following stimulation with tumor necrosis factor (TNF), lipopolysaccharide (LPS; Toll-like receptor 4 (TLR4) ligand), and polyinosinic: polycytidylic acid (pIC; TLR3 ligand). Whereas induction of proinflammatory genes such as interleukin-8 (IL-8) required only RelA, pIgR expression was regulated by complex mechanisms that involved both RelA and RelB. Upregulation of pIgR expression by ligation of the lymphotoxin-β receptor suggested a direct role for the alternative NF-κB pathway. Inhibition of mitogen-activated protein kinases reduced the induction of IL-8, but enhanced the induction of pIgR by TNF and TLR signaling. Regulation of pIgR through unique signaling pathways could allow IECs to sustain high levels of IgA transport while limiting the proinflammatory responses

Определение рациональных компоновочных решений для аппарата воздушного охлаждения масла систем смазки компрессорных установок с использованием методов физического и численного моделирования

The objective of the present work was to study heat and hydraulic parameters of an air cooling apparatus of oil (ACAO), whose geometry of its flow-through part is changed to decrease hydraulic losses in its air conduit and to increase the cooling efficiency of oil. Using numerical simulation methods of heat transfer, we have developed and tested the computational techniques applied in a wide class of heat exchange apparatuses, including those consisting of the sections of finned flat tubes manufactured by extrusion with subsequent deforming cutting. We have proposed to make a finned part of a heat-exchange surface in the form of porous inserts. This has allowed us to reduce numerical simulation equipment requirements and to decrease computational time. Predicted results well agree with experimental data; their analysis shows that the calculated value of thermal performance of the oil cooler due to the revealed construction drawbacks of the air conduit is by 19 % less than that of the designed one. Based on the results of the numerical simulation studies, a number of recommendations have been made how to improve the layout inside the air cooling apparatus for oil in order to enhance its thermal performance and aerodynamic quality. In particular, we have proposed to mount new fan blades to enhance its performance; to change the construction of the air outlet valve by taking away a baffle that partially overshadows the exit area of the bottom fan; to modify the shape of the bottom collector of the oil cooler in order to make a uniform velocity profile at the entrance of cooling sections. Connecting in series heat exchange sections may be a perspective engineering decision. The outcomes of all proposed engineering decisions can be assessed by numerical simulation methods that will allow us not to design expensive equipment.С помощью методов численного моделирования исследованы тепло- и гидравлические параметры аппаратов воздушного охлаждения масла (АВОМ) при изменении геометрии проточной части для снижения аэродинамического сопротивления воздушного тракта АВОМ и повышения эффективности охлаждения масла. Для этого на основе методов численного моделирования конвективного теплообмена разработана и апробирована методика расчетов, применимая к широкому классу теплообменных аппаратов, в том числе состоящих из секций оребренных плоских труб, полученных методом экструзии с последующей обработкой методом деформирующего резания. Отличительной особенностью методики является представление оребренной части теплопередающей поверхности в виде пористых вставок. Разработанная методика позволяет уменьшить требования к оборудованию для численного моделирования и снизить время расчетов. Результаты численного моделирования хорошо согласуются с результатами эксперимента; их анализ показывает, что тепловая мощность маслоохладителя вследствие выявленных конструктивных недостатков воздушного тракта АВОМ на 19 % меньше проектного значения. На основе численных исследований выработан ряд рекомендаций по дальнейшему совершенствованию компоновочных решений для аппарата воздушного охлаждения масла с целью повышения его тепловой эффективности и аэродинамического совершенства. В частности, предложено установить новые лопатки вентиляторов для повышения их производительности; изменить конструкцию выходного воздушного клапана (жалюзи), исключив перегородку, частично затеняющую проходное сечение нижнего вентилятора; изменить форму нижнего коллектора маслоохладителя с целью обеспечения равномерного профиля скорости на входе в охлаждающие секции. Перспективным техническим решением, приводящим к увеличению общей производительности маслоохладителя, может быть последовательная схема подключения теплообменных секций. Эффективность всех предложенных технических решений может быть оценена с помощью методов численного моделирования, без создания дорогостоящей пилотной установки