Selective Preservation of Bone Marrow Mature Recirculating but Not Marginal Zone B Cells in Murine Models of Chronic Inflammation

Inflammation promotes granulopoiesis over B lymphopoiesis in the bone marrow (BM). We studied B cell homeostasis in two murine models of T cell mediated chronic inflammation, namely calreticulin-deficient fetal liver chimeras (FLC), which develop severe blepharitis and alopecia due to T cell hyper responsiveness, and inflammatory bowel disease (IBD) caused by injection of CD4+ naïve T cells into lymphopenic mice. We show herein that despite the severe depletion of B cell progenitors during chronic, peripheral T cell-mediated inflammation, the population of BM mature recirculating B cells is unaffected. These B cells are poised to differentiate to plasma cells in response to blood borne pathogens, in an analogous fashion to non-recirculating marginal zone (MZ) B cells in the spleen. MZ B cells nevertheless differentiate more efficiently to plasma cells upon polyclonal stimulation by Toll-like receptor (TLR) ligands, and are depleted during chronic T cell mediated inflammation in vivo. The preservation of mature B cells in the BM is associated with increased concentration of macrophage migration inhibitory factor (MIF) in serum and BM plasma. MIF produced by perivascular dendritic cells (DC) in the BM provides a crucial survival signal for recirculating B cells, and mice treated with a MIF inhibitor during inflammation showed significantly reduced mature B cells in the BM. These data indicate that MIF secretion by perivascular DC may promote the survival of the recirculating B cell pool to ensure responsiveness to blood borne microbes despite loss of the MZ B cell pool that accompanies depressed lymphopoiesis during inflammation

Parameterization of a coarse-grained model of cholesterol with point-dipole electrostatics

© 2018, Springer Nature Switzerland AG. We present a new coarse-grained (CG) model of cholesterol (CHOL) for the electrostatic-based ELBA force field. A distinguishing feature of our CHOL model is that the electrostatics is modeled by an explicit point dipole which interacts through an ideal vacuum permittivity. The CHOL model parameters were optimized in a systematic fashion, reproducing the electrostatic and nonpolar partitioning free energies of CHOL in lipid/water mixtures predicted by full-detailed atomistic molecular dynamics simulations. The CHOL model has been validated by comparison to structural, dynamic and thermodynamic properties with experimental and atomistic simulation reference data. The simulation of binary DPPC/cholesterol mixtures covering the relevant biological content of CHOL in mammalian membranes is shown to correctly predict the main lipid behavior as observed experimentally

Small-molecule inhibitors of macrophage migration inhibitory factor(MIF) as an emerging class of therapeutics for immune disorders

Macrophage migration inhibitory factor (MIF) is an important cytokine for which an increasing number of functions is being described in the pathogenesis of inflammation and cancer. Nevertheless, the availability of potent and druglike MIF inhibitors that are well-characterized in relevant disease models remains limited. Development of highly potent and selective small-molecule MIF inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we provide an overview of recent advances in the identification of MIF as a pharmacological target in the pathogenesis of inflammatory diseases and cancer. We also give an overview of the current developments in the discovery and design of small-molecule MIF inhibitors and define future aims in this fiel

Magnetic nanoparticles coated with polyarabic acid demonstrate enhanced drug delivery and imaging properties for cancer theranostic applications

Therapeutic targeting of tumor cells with drug nanocarriers relies upon successful interaction with membranes and efficient cell internalization. A further consideration is that engineered nanomaterials should not damage healthy tissues upon contact. A critical factor in this process is the external coating of drug delivery nanodevices. Using in silico, in vitro and in vivo studies, we show for the first time that magnetic nanoparticles coated with polyarabic acid have superior imaging, therapeutic, and biocompatibility properties. We demonstrate that polyarabic acid coating allows for efficient penetration of cell membranes and internalization into breast cancer cells. Polyarabic acid also allows reversible loading of the chemotherapeutic drug Doxorubicin, which upon release suppresses tumor growth in vivo in a mouse model of breast cancer. Furthermore, these nanomaterials provide in vivo contrasting properties, which directly compare with commercial gadolinium-based contrasting agents. Finally, we report excellent biocompatibility, as these nanomaterial cause minimal, if any cytotoxicity in vitro and in vivo. We thus propose that magnetic nanodevices coated with polyarabic acid offer a new avenue for theranostics efforts as efficient drug carriers, while providing excellent contrasting properties due to their ferrous magnetic core, which can help the future design of nanomaterials for cancer imaging and therapy. © 2017 The Author(s)

A research on human body symbols as a meansof expression for contemporary ceramıc(s) art

Bu araştırma insan bedeni sembollerinin seramikte kullanımı ve çağdaş seramik sanatçılarının eserleriyle değerlendirilmeye çalışılmıştır. Tarih öncesi çağlarda ilk insanın mağara duvarlarına çizdiği resimler sembolik bir arayışın ürünleri olarak ortaya çıkmıştır. Bu sembolik ifadeler; insanın doğadan edindiği izlenimlerle birlikte, sanatın temelini oluşturmuştur. Bu bağlamda insan, çevresiyle etkileşime geçtiğinde duygu ve düşüncelerini, aklını kullanarak, bu birlikten doğan sonuçla sembolleri yaşamının her alanında kullanmaya başlamıştır. Sembolik düşünmeye başlayan insan kendi bedenini ve diğer bedenleri keşfetmeye başlar. Onu algılayabilmek, öğrenmek ve şekillendirebilmek ancak onu en iyi şekilde tanımayla kazanılır. Duygu ve düşünceleri sembollerle ifade etme anlayışı insanlar için bir anlamda ihtiyaçtır. Sembolik düşünmeyi başarabilen insan, yine duygu ve düşüncelerini aktarırken soyut olanı somutlama yolunda ilerlerken sembollerle anlatabilme yetisine sahiptir. Beden belli bir zamana, toplumsal işleyişe ve alana işaret eder. İnsan ve insan bedeni sembollerinin en eskisi ve en evrenseli olması da bundan kaynaklanır. İnsan bedeni yaşamı, ölümü, cinselliği içinde barındırdığı için yaşamın somutlaştığı bir alan haline de gelmektedir. Bu somutlaşmayı sağlayan insanoğlu, sembolleri kullanarak insan bedenini daha okunur hale getirmiştir. İnsan bedeninin belli bölümlerinin sembolik ifadeye dökülmesi, anlam ve dönemsel özelliklerinin bilinmesi ve bu anlamda çağdaş seramik sanatçılarının eserleri, yeni bir yönelim ve bakış açısı kazanma sağlaması açısından önem taşımaktadır.This research has been tried to be evaluated with the usage of the symbols of human body on ceramics and the works of contemporary ceramic artists. The images that were drawn on the cave walls by the primitive men in the prehistoric ages emerged as the products of a symbolic quest. These symbolic expressions, together with the impressions taken from the nature by men, generated the basis of art. In this regard, humans, upon using their minds, emotions, and thoughts while interacting their surroundings, started using the symbols that were born out of this unity on every field of life. A human that starts thinking symbolically discovers his body and then other bodies. Sensing, learning and shaping it can only be achieved by getting to know it ideally. In a sense, the conception of expressing the emotions and thoughts via symbols is a necessity for humans. Humans that achieve to think symbolically also have the ability to use symbols on transmitting their emotions and thoughts while concreting what is abstract. The body points out to a certain time period, social functioning and area. This is the reason why the human body symbols are the oldest and most universal ones. Human and also becomes a field in which the life turns concrete since it contains life, death and sexuality. The human and human being that has procured this concretization made the human body more legible by using symbols. With regards to symbolically articulating the human and certain parts of human body and getting to know their meanings and their periodical features, works of contemporary ceramic artists are essential in order to be able to gain new tendencies and perspectives

A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a homotrimeric multifunctional proinflammatory cytokine that has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Current therapeutic strategies for targeting MIF focus on developing inhibitors of its tautomerase activity or modulating its biological activities using anti-MIF neutralizing antibodies. Herein we report a new class of isothiocyanate (ITC)-based irreversible inhibitors of MIF. Modification by benzyl isothiocyanate (BITC) and related analogues occurred at the N-terminal catalytic proline residue without any effect on the oligomerization state of MIF. Different alkyl and arylalkyl ITCs modified MIF with nearly the same efficiency as BITC. To elucidate the mechanism of action, we performed detailed biochemical, biophysical, and structural studies to determine the effect of BITC and its analogues on the conformational state, quaternary structure, catalytic activity, receptor binding, and biological activity of MIF. Light scattering, analytical ultracentrifugation, and NMR studies on unmodified and ITC-modified MIF demonstrated that modification of Pro1 alters the tertiary, but not the secondary or quaternary, structure of the trimer without affecting its thermodynamic stability. BITC induced drastic effects on the tertiary structure of MIF, in particular residues that cluster around Pro1 and constitute the tautomerase active site. These changes in tertiary structure and the loss of catalytic activity translated into a reduction in MIF receptor binding activity, MIF-mediated glucocorticoid overriding, and MIF-induced Akt phosphorylation. Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo

A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a homotrimeric multifunctional proinflammatory cytokine that has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Current therapeutic strategies for targeting MIF focus on developing inhibitors of its tautomerase activity or modulating its biological activities using anti-MIF neutralizing antibodies. Herein we report a new class of isothiocyanate (ITC)-based irreversible inhibitors of MIF. Modification by benzyl isothiocyanate (BITC) and related analogues occurred at the N-terminal catalytic proline residue without any effect on the oligomerization state of MIF. Different alkyl and arylalkyl ITCs modified MIF with nearly the same efficiency as BITC. To elucidate the mechanism of action, we performed detailed biochemical, biophysical, and structural studies to determine the effect of BITC and its analogues on the conformational state, quaternary structure, catalytic activity, receptor binding, and biological activity of MIF. Light scattering, analytical ultracentrifugation, and NMR studies on unmodified and ITC-modified MIF demonstrated that modification of Pro1 alters the tertiary, but not the secondary or quaternary, structure of the trimer without affecting its thermodynamic stability. BITC induced drastic effects on the tertiary structure of MIF, in particular residues that cluster around Pro1 and constitute the tautomerase active site. These changes in tertiary structure and the loss of catalytic activity translated into a reduction in MIF receptor binding activity, MIF-mediated glucocorticoid overriding, and MIF-induced Akt phosphorylation. Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo