Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats

Blocking the action of inhibitory molecules at sites of central nervous system injury has been proposed as a strategy to promote axonal regeneration and functional recovery. We have previously shown that genetic deletion or competitive antagonism of EphA4 receptor activity promotes axonal regeneration and functional recovery in a mouse model of lateral hemisection spinal cord injury. Here we have assessed the effect of blocking EphA4 activation using the competitive antagonist EphA4-Fc in a rat model of thoracic contusive spinal cord injury. Using a ledged tapered balance beam and open-field testing, we observed significant improvements in recovery of locomotor function after EphA4-Fc treatment. Consistent with functional improvement, using high-resolution ex vivo magnetic resonance imaging at 16.4T, we found that rats treated with EphA4-Fc had a significantly increased cross-sectional area of the dorsal funiculus caudal to the injury epicenter compared with controls. Our findings indicate that EphA4-Fc promotes functional recovery following contusive spinal cord injury and provides further support for the therapeutic benefit of treatment with the competitive antagonist in acute cases of spinal cord injury

Killing of Escherichia coli by Crohn's Disease Monocyte-derived Macrophages and Its Enhancement by Hydroxychloroquine and Vitamin D

BACKGROUND: Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly adherent and invasive Escherichia coli that replicate inside macrophage phagolysosomes. We compared CD and healthy control (HC) macrophages for their abilities to kill E. coli and generate neutrophil chemoattractants and also assessed the effects of hydroxychloroquine (HCQ) and vitamin D on killing of phagocytosed E. coli. METHODS: Peripheral blood monocyte-derived macrophages from CD and HC were compared for bacterial killing and generation of neutrophil chemoattractants in response to CD-derived E. coli. Escherichia coli replication was also assessed in the presence and absence of HCQ, alone and with antibiotics, and vitamin D. RESULTS: Monocyte-derived macrophages from patients with CD were similar to HC in allowing replication of phagocytosed CD-derived E. coli: HM605 {CD: N = 10, mean fold replication in 3 hr = 1.08 (95% confidence interval [CI], 0.39–1.78); HC: N = 9, 1.50 (95% CI, 1.02–1.97); P = 0.15} and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD = 2.55 [95% CI, 2.31–2.80]; HC = 2.65 [95% CI, 2.46–2.85], P = 0.42). HCQ and 1,25 OH(2)-vitamin D(3) both caused dose-dependent inhibition of intramacrophage E. coli replication 3-hour postinfection; HCQ: 73.9% inhibition (P < 0.001) at 1 μg/mL, accompanied by raised intraphagosomal pH, and 1,25 OH(2)-vitamin D(3): 80.7% inhibition (P < 0.05) at 80 nM. HCQ had synergistic effects with doxycycline and ciprofloxacin. CONCLUSIONS: CD and HC macrophages perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics

One-step zero-background IgG reformatting of phage-displayed antibody fragments enabling rapid and high-throughput lead identification

 A superconducting pair in high-temperature superconductivity structure was supposed to have an electrical quadrupole moment. It was shown, that under certain conditions, at the part of acoustic phonons, conduction electrons in high-temperature superconductivity structure can form superconducting pairs, when the interaction energy of the quadrupole moment of a superconducting pair with the structure electric field exceeds the energy of Coulomb repulsion between electrons. The electrical field parameters in a CuO2 plane of high-temperature superconductivity structure have been obtained by the method of effective point charges. The distance between electrons in superconducting pair in a CuO2 plane have been estimated in ~ 75 ÷ 130 Å. Within the framework of the suggested model it was shown that high-temperature superconductivity IR-spectra, which were observed at 500 cm-1, can be caused by the quadrupole resonance of superconducting pairs. Выдвинуто предположение, что электрический квадрупольный момент куперовской пары в структуре высокотемпературных сверхпроводников отличен от нуля. Показано, что при определенных условиях при участии акустических фононов электроны проводимости в структуре высокотемпературных сверхпроводников могут образовывать куперовские пары, когда энергия взаимодействия квадрупольного момента куперовской пары превышает энергию кулоновского отталкивания между электронами. Параметры электрического поля в плоскости CuO2 в высокотемпературных сверхпроводниках рассчитаны методом эффективных точечных зарядов. Расстояние между электронами в куперовской паре в плоскости CuO2 равно ~ 75 ÷ 130 Å. В соответствии с предлагаемой моделью инфракрасные спектры, наблюдаемые в районе 500 см-1 для высокотемпературных сверхпроводников, могут быть обусловлены квадрупольным резонансом куперовских пар. Висунуто припущення, що електричний квадрупольний момент куперівської пари в структурі високо-температурних надпровідників відмінний від нуля. Показано, що за певних умов за участю акустичних фононів електрони провідності в структурі високотемпературних надпровідників можуть утворювати куперівські пари, коли енергія взаємодії квадрупольного моменту куперівської пари перевищує енергію кулонівського відштовхування між електронами. Параметри електричного поля в площині CuО2 у високотемпературних надпровідниках розраховані методом ефективних точкових зарядів. Відстань між електронами в куперівській парі в площині CuО2 становить 75–130 Å. Відповідно до запропонованої моделі показано, що інфрачервоні спектри, які спостерігаються в районі 500 см-1 для високотемпера-турних надпровідників, можуть бути обумовлені квадрупольним резонансом куперівських пар

Variability of PCB burden in 5 fish and sharks species of the French Mediterranean continental slope

Despite being generally located far from contamination sources, deep marine ecosystems are impacted by chemicals like PCB. The PCB contamination in five fish and shark species collected in the continental slope of the Gulf of Lions (NW Mediterranean Sea) was measured, with a special focus on intra- and interspecific variability and on the driving factors. Significant differences occurred between species. Higher values were measured in Scyliorhinus canicula, Galeus melastomus and Helicolenus dactylopterus and lower values in Phycis blennoides and Lepidorhombus boscii. These differences might be explained by specific abilities to accumulate and eliminate contaminant, mostly through cytochrome P450 pathway. Interindividual variation was also high and no correlation was observed between contamination and length, age or trophic level. Despite its major importance, actual bioaccumulation of PCB in deep fish is not as documented as in other marine ecosystems, calling for a better assessment of the factors driving individual bioaccumulation mechanisms and originating high variability in PCB contamination

La constitution au tournant des XXe et XXIe siècles

Face à la récurrence actuelle de la thématique de la « crise de confiance » des démocraties représentatives et dans le contexte des anniversaires respectifs de la Constitution de la République de Weimar (1919), de la Loi fondamentale de la République fédérale allemande (1949) et de la Constitution française de la Ve République (1958), ce dossier thématique propose une mise en perspective historique, théorique et comparée de la notion de constitution et une réflexion sur ses acteurs et sur son avenir dans un environnement social et politique fragmenté. Ce numéro a été réalisé avec l’aide de la Délégation générale à la langue française et aux langues de France (Ministère de la Culture), des Éditions de la Maison des sciences de l’homme et de la Fondation Fritz Thyssen (Cologne). Angesichts der »Vertrauenskrise«, mit der sich die repräsentativen Demokratien jüngst wieder konfrontiert sehen, und vor dem Hintergrund der gegenwärtigen Gedenkjahre anlässlich der Verabschiedungen der Verfassung der Weimarer Republik (1919) vor 100 Jahren, des Grundgesetzes der Bundesrepublik Deutschland (1949) vor 50 und der Verfassung der V. Französischen Republik (1958) vor 60 Jahren geht es in diesem Themenheft um historische, theoretische und vergleichende Analysen des Begriffs der Verfassung, sowie um Überlegungen zu ihren Akteuren und zu ihrer Zukunft in einem fragmentierten sozialen und politischen Umfeld. Diese Publikation wurde gefördert durch die Fritz Thyssen Stiftung (Köln), die Éditions de la Maison des sciences de l’homme und die Délégation générale à la langue française et aux langues de France (Paris)

Primary structure of ovine pituitary basic fibroblast growth factor

AbstractThe complete amino acid sequence of basic FGF (146 residues) from ovine pituitary glands has been established. This has been achieved by the sequence analysis of subnanomole amounts of the intact molecule and of peptides derived by enzymatic digestions with clostripain, chymotrypsin, pepsin and Staphylococcus aureus V8 protease. Microbore HPLC, employing 1–2 mm i.d. columns, was used to purify, concentrate and buffer-exchange the FGF peptides. A novel application of ion-pairing chromatography was employed to isolate peptides which were not retained on conventional reversed-phase systems. There is only one positional difference between the ovine and bovine basic FGFs, but there are 3 positional differences between ovine and human basic FGFS

An optimized hepatitis C virus E2 glycoprotein core adopts a functional homodimer that efficiently blocks virus entry

The hepatitis C virus (HCV) envelope glycoprotein E2 is the major target of broadly neutralizing antibodies in vivo and is the focus of efforts in the rational design of a universal B cell vaccine against HCV. The E2 glycoprotein exhibits a high degree of amino acid variability which localizes to three discrete regions: hypervariable region 1 (HVR1), hypervariable region 2 (HVR2), and the intergenotypic variable region (igVR). All three variable regions contribute to immune evasion and/or isolate-specific structural variations, both important considerations for vaccine design. A high-resolution structural definition of the intact HCV envelope glycoprotein complex containing E1 and E2 remains to be elucidated, while crystallographic structures of a recombinant E2 ectodomain failed to resolve HVR1, HVR2, and a major neutralization determinant adjacent to HVR1. To obtain further information on E2, we characterized the role of all three variable regions in E2 ectodomain folding and function in the context of a recombinant ectodomain fragment (rE2). We report that removal of the variable regions accelerates binding to the major host cell receptor CD81 and that simultaneous deletion of HVR2 and the igVR is required to maintain wild-type CD81-binding characteristics. The removal of the variable regions also rescued the ability of rE2 to form a functional homodimer. We propose that the rE2 core provides novel insights into the role of the variable motifs in the higher-order assembly of the E2 ectodomain and may have implications for E1E2 structure on the virion surface. IMPORTANCE Hepatitis C virus (HCV) infection affects ∼2% of the population globally, and no vaccine is available. HCV is a highly variable virus, and understanding the presentation of key antigenic sites at the virion surface is important for the design of a universal vaccine. This study investigates the role of three surface-exposed variable regions in E2 glycoprotein folding and function in the context of a recombinant soluble ectodomain. Our data demonstrate the variable motifs modulate binding of the E2 ectodomain to the major host cell receptor CD81 and have an impact on the formation of an E2 homodimer with high-affinity binding to CD81

Emergence of immunosuppressive LOX-1+ PMN-MDSC in septic shock and severe COVID-19 patients with acute respiratory distress syndrome

International audienceMyeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with immunosuppressive properties. In cancer patients, the expression of lectin-type oxidized LDL receptor 1 (LOX-1) on granulocytic MDSC identifies a subset of MDSC that retains the most potent immunosuppressive properties. The main objective of the present work was to explore the presence of LOX-1+ MDSC in bacterial and viral sepsis. To this end, whole blood LOX-1+ cells were phenotypically, morphologically, and functionally characterized. They were monitored in 39 coronavirus disease-19 (COVID-19, viral sepsis) and 48 septic shock (bacterial sepsis) patients longitudinally sampled five times over a 3 wk period in intensive care units (ICUs). The phenotype, morphology, and immunosuppressive functions of LOX-1+ cells demonstrated that they were polymorphonuclear MDSC. In patients, we observed the significant emergence of LOX-1+ MDSC in both groups. The peak of LOX-1+ MDSC was 1 wk delayed with respect to ICU admission. In COVID-19, their elevation was more pronounced in patients with acute respiratory distress syndrome. The persistence of these cells may contribute to long lasting immunosuppression leaving the patient unable to efficiently resolve infections