Junctional adhesion molecule-A deficient mice are protected from severe experimental autoimmune encephalomyelitis.

In multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), early pathological features include immune cell infiltration into the central nervous system (CNS) and blood-brain barrier (BBB) disruption. We investigated the role of junctional adhesion molecule-A (JAM-A), a tight junction protein, in active EAE (aEAE) pathogenesis. Our study confirms JAM-A expression at the blood-brain barrier and its luminal redistribution during aEAE. JAM-A deficient (JAM-A-/-) C57BL/6J mice exhibited milder aEAE, unrelated to myelin oligodendrocyte glycoprotein-specific CD4+ T-cell priming. While JAM-A absence influenced macrophage behavior on primary mouse brain microvascular endothelial cells (pMBMECs) under flow in vitro, it did not impact T-cell extravasation across primary mouse brain microvascular endothelial cells. At aEAE onset, we observed reduced lymphocyte and CCR2+ macrophage infiltration into the spinal cord of JAM-A-/- mice compared to control littermates. This correlated with increased CD3+ T-cell accumulation in spinal cord perivascular spaces and brain leptomeninges, suggesting JAM-A absence leads to T-cell trapping in central nervous system border compartments. In summary, JAM-A plays a role in immune cell infiltration and clinical disease progression in aEAE

An AIF orthologue regulates apoptosis in yeast

Apoptosis-inducing factor (AIF), a key regulator of cell death, is essential for normal mammalian development and participates in pathological apoptosis. The proapoptotic nature of AIF and its mode of action are controversial. Here, we show that the yeast AIF homologue Ynr074cp controls yeast apoptosis. Similar to mammalian AIF, Ynr074cp is located in mitochondria and translocates to the nucleus of yeast cells in response to apoptotic stimuli. Purified Ynr074cp degrades yeast nuclei and plasmid DNA. YNR074C disruption rescues yeast cells from oxygen stress and delays age-induced apoptosis. Conversely, overexpression of Ynr074cp strongly stimulates apoptotic cell death induced by hydrogen peroxide and this effect is attenuated by disruption of cyclophilin A or the yeast caspase YCA1. We conclude that Ynr074cp is a cell death effector in yeast and rename it AIF-1 (Aif1p, gene AIF1)

Телемедицина: перспективы развития

Необходимость развития в условиях цифровой экономики такого направления как телемедицина кажется необходимостью, однако существует противоречие между существующими проблемами в системе организации здравоохранения Российской Федерации и возможностями доступности к услугам телемедицины. Анализ показал, что данное направление востребовано, необходимо, существует ряд сервисов, предлагающих услуги по телемедицине, однако нормативно-правовая база не позволяет в полной мере организовать полноценную работу по предоставлению телемедицинских услуг, в том числе, бесплатных

PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-Cell diapedesis across the blood-brain barrier during neuroinflammation

Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical grey matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance

Migration of cytotoxic lymphocytes in cell cycle permits local MHC I–dependent control of division at sites of viral infection

Virus-specific cytotoxic CD8+ T cells are in cell cycle as they transit from lymphoid tissues to sites of infection

Peripheral blood biomarkers in multiple sclerosis.

Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. The heteroge-neity of pathophysiological processes in MS contributes to the highly variable course of the disease and unpre-dictable response to therapies. The major focus of the research on MS is the identification of biomarkers inbiologicalfluids, such as cerebrospinalfluid or blood, to guide patient management reliably. Because of the diffi-culties in obtaining spinalfluid samples and the necessity for lumbar puncture to make a diagnosis has reduced,the research of blood-based biomarkers may provide increasingly important tools for clinical practice. However,currently there are no clearly established MS blood-based biomarkers. The availability of reliable biomarkerscould radically alter the management of MS at critical phases of the disease spectrum, allowing for interventionstrategies that may prevent evolution to long-term neurological disability. This article provides an overview ofthis researchfield and focuses on recent advances in blood-based biomarker researc

Late Stage Infection in Sleeping Sickness

At the turn of the 19th century, trypanosomes were identified as the causative agent of sleeping sickness and their presence within the cerebrospinal fluid of late stage sleeping sickness patients was described. However, no definitive proof of how the parasites reach the brain has been presented so far. Analyzing electron micrographs prepared from rodent brains more than 20 days after infection, we present here conclusive evidence that the parasites first enter the brain via the choroid plexus from where they penetrate the epithelial cell layer to reach the ventricular system. Adversely, no trypanosomes were observed within the parenchyma outside blood vessels. We also show that brain infection depends on the formation of long slender trypanosomes and that the cerebrospinal fluid as well as the stroma of the choroid plexus is a hostile environment for the survival of trypanosomes, which enter the pial space including the Virchow-Robin space via the subarachnoid space to escape degradation. Our data suggest that trypanosomes do not intend to colonize the brain but reside near or within the glia limitans, from where they can re-populate blood vessels and disrupt the sleep wake cycles

Coming full circle: constructing a [Gd6] wheel dimer by dimer and the importance of spin topology

© 2017 The Royal Society of Chemistry. The syntheses, structures, magnetic and thermodynamic properties of three related triethanolamine-based Gd III complexes are described. The smallest, a dimer ([Gd 2 ]), can be viewed as the subunit from which the two larger complexes, a linear tetramer ([Gd 2 ] 2 ) and a cyclic hexamer ([Gd 2 ] 3 ), are composed by further deprotonation of the triethanolamine ligand. In all cases, nearest neighbour magnetic ions are weakly correlated by antiferromagnetic isotropic exchange, whose strength does not change significantly from one complex to another; J ranging from -0.10 to -0.13 cm -1 . Therefore, rather than the strength of the coupling, it is the spin topology that is the dominant factor in determining the differences between the physical properties-specifically, the nuclearity and the transition from open (dimer and tetramer) to cyclic (hexamer) boundary conditions. Indeed the hexanuclear wheel reaches the continuum limit of classical Heisenberg spin chains. In terms of the magnetocaloric properties, the smaller the nuclearity, the larger the magnetic entropy and adiabatic temperature changes

Plants in aquatic ecosystems: current trends and future directions

Aquatic plants fulfil a wide range of ecological roles, and make a substantial contribution to the structure, function and service provision of aquatic ecosystems. Given their well-documented importance in aquatic ecosystems, research into aquatic plants continues to blossom. The 14th International Symposium on Aquatic Plants, held in Edinburgh in September 2015, brought together 120 delegates from 28 countries and six continents. This special issue of Hydrobiologia includes a select number of papers on aspects of aquatic plants, covering a wide range of species, systems and issues. In this paper we present an overview of current trends and future directions in aquatic plant research in the early 21st century. Our understanding of aquatic plant biology, the range of scientific issues being addressed and the range of techniques available to researchers have all arguably never been greater; however, substantial challenges exist to the conservation and management of both aquatic plants and the ecosystems in which they are found. The range of countries and continents represented by conference delegates and authors of papers in the special issue illustrate the global relevance of aquatic plant research in the early 21st century but also the many challenges that this burgeoning scientific discipline must address

Identification and characterization of mitochondrial signaling pathways as core regulators of apoptosis in Saccharomyces cerevisiae

Apoptose ist eine evolutionär konservierte Form des programmierten Zelltodes, die zunächst in dem Fadenwurm Caenorhabditis elegans und in Zellkulturen untersucht wurde. Die Entdeckung morphologischer Merkmale der Apoptose in Hefe sowie die Identifizierung einer Hefecaspase ließen diesen einzelligen Eukaryonten zu einem möglichen Modellorganismus für die Erforschung der Apoptose werden. Mitochondrien sind nicht nur die Energieerzeuger, sondern auch die „Waffenkammer“ der Zelle. Mitochondriale Cytochrom c-Ausschüttung in das Cytosol ist ein wichtiger Bestandteil des apoptotischen Signalweges in Säugerzellen. In dieser Arbeit wird nachgewiesen, dass die Mitochondrien auch bei der Hefeapoptose beteiligt sind. Bei der Induktion von Apoptose durch Überexpression der Hefecaspase Yca1p (Yeast Caspase 1) konnte eine Ausschüttung von Cytochrom c aus den Mitochondrien ins Cytosol beobachtet werden. Überdies ist die Caspase in Nullmutanten der beiden Isoformen von Cytochrom c in Saccharomyces cerevisiae nicht mehr in der Lage, ihre todbringende Wirkung zu entfalten. Umgekehrt wird durch eine Überexpression von Cyc1p, der unter aeroben Bedingungen exprimierten Isoform von Cytochrom c, eine verringerte Überlebensfähigkeit von S. cerevisiae hervorgerufen, was wiederum durch die Deletion des Hefegens YCA1 verhindert werden kann. Schließlich konnte gezeigt werden, dass für die Yca1p-vermittelte Apoptose eine intakte Atmungskette benötigt wird.Apoptosis is an evolutionary conserved form of cell death on which research was primarily performed in the nematode Caenorhabditis elegans and in cell culture. Discovery of a mutant with morphological markers of apoptosis as well as identification of a yeast caspase made yeast a potential research tool for apoptosis. Mitochondria are not only the energy sources of cells but also “the armoury”. Cytochrome c release from mitochondria is a key player in the mammalian apoptotic pathway. In this thesis it is shown, that mitochondria also partake in yeast apoptosis. Induction of apoptosis through overexpression of yeast caspase Yca1p (Yeast Caspase 1) led to release of cytochrome c from mitochondria into the cytosol. Moreover, null mutants of either isoform 1 or 2 of cytochrome c in Saccharomyces cerevisiae are insensitive towards apoptosis induction through the yeast caspase. On the other hand, overexpression of Cyc1p, the cytochrome c isoform being expressed under aerobic conditions, decreases survival of S. cerevisiae, which can be prevented by deletion of the yeast gene YCA1. Finally, it could be shown, that Yca1p mediated apoptosis depends on a functionally intact respiratory chain