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991.
Ali H. Ellebedy Florian Krammer Gui-Mei Li Matthew S. Miller Christopher Chiu Jens Wrammert Cathy Y. Chang Carl W. Davis Megan McCausland Rivka Elbein Srilatha Edupuganti Paul Spearman Sarah F. Andrews Patrick C. Wilson Adolfo García-Sastre Mark J. Mulligan Aneesh K. Mehta Peter Palese Rafi Ahmed 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(36):13133-13138
The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.The emergence of novel influenza virus strains poses a continuous public health threat (1, 2). The World Health Organization estimates that influenza viruses infect one-billion people annually, with three- to five-million cases of severe illness, and up to 500,000 deaths worldwide (3). Following influenza virus infection, humoral immune responses against the viral hemagglutinin (HA) protein may persist for decades in humans (4). These anti-HA responses correlate strongly with protection against influenza infection (5). Serological memory is maintained by antibody-secreting long-lived plasma cells and reinforced by memory B cells, which can rapidly differentiate into antibody-secreting cells upon antigen reexposure (6).Influenza vaccine efficacy is constantly undermined by antigenic variation in the circulating viral strains, particularly in the HA and neuraminidase (NA) proteins. Current influenza vaccination strategies rely on changing the HA and NA components of the annual human vaccine to ensure that they antigenically match circulating influenza strains (7, 8). Developing an influenza vaccine that is capable of providing broad and long-lasting protective antibody responses remains the central challenge for influenza virus research.HA is a trimer, with each monomer comprised of two subunits: HA1, which includes the HA globular head, and HA2, whose ectodomain together with the N- and C-terminal parts of HA1 constitute the HA stem region (9). Phylogenetically, the 18 HA subtypes characterized so far are divided into two groups. Among strains that have recently caused disease in humans, H1 and H5 HAs belong to group 1, whereas H3 and H7 HAs belong to group 2 (10). Conventional anti-HA neutralizing antibodies primarily target a few immunodominant epitopes located in proximity to the receptor-binding domain within the globular head region of the molecule (11, 12). Although these antibodies are potentially protective, they are strain-specific because of the high variability of such epitopes, and thus lack, in general, the much-desired broad neutralizing activity. Recently, broadly neutralizing human (13–18) and murine (19) monoclonal antibodies (mAbs) directed against distinct epitopes within the HA stem region have been extensively characterized. These mAbs were shown to interfere with the influenza viruses’ life cycle in different ways (20). By generating monoclonal antibodies from plasmablasts isolated ex vivo, we demonstrated that these broadly neutralizing antibodies could be retrieved from patients infected with or vaccinated against the pandemic H1N1 2009 influenza virus (18, 21). Recent observations that HA stem epitopes are accessible on the majority of HA trimers on intact virions (22), and that a stable HA stem protein that is immunologically intact could be produced (23), provided further hope for the feasibility of a stem-based universal influenza vaccine (24).Notably, HA stem-specific mAbs isolated from humans showed a high degree of affinity maturation, suggesting a memory B-cell origin. These results raised two important questions that we address in the current study. First, what are the baseline levels of broadly cross-reactive stem-binding antibodies and memory B cells? Second, using current influenza vaccines, to what extent can HA stem-specific responses be boosted in comparison with those directed against the HA globular head?Structural studies have clearly demonstrated that the main neutralizing antibody epitopes within the HA stem region are conformation-dependent, and that the integrity of these epitopes requires the presence of the HA1 subunit in addition to the HA2 subunit, which constitute the bulk of the HA stem (16, 17). To be able to directly measure HA stem-reactive antibodies and memory B cells, we used a chimeric HA molecule that expresses the globular head of H9 HA on H1 backbone (25). Our data demonstrate that post-2009 trivalent inactivated vaccines (TIV) induced minimal stem-specific responses in comparison with head-specific responses. On the other hand, immunization with H5N1 generated relatively strong anti-HA stem responses, demonstrating that it is feasible to elicit broadly neutralizing responses in humans given the right immunogen design. 相似文献
992.
Du Cailian Wu Jianhui Bashir Muhammad Hamid Shaukat Mobeen Ali Shaukat 《Ecotoxicology (London, England)》2019,28(4):422-428
Ecotoxicology - Contamination of environment with heavy metals is increasingly becoming an issue of major concern across the globe. Heavy metals are highly toxic to humans as well as other... 相似文献
993.
Shigeki Kawai Matthias Koch Enrico Gnecco Ali Sadeghi Rémy Pawlak Thilo Glatzel Jutta Schwarz Stefan Goedecker Stefan Hecht Alexis Baratoff Leonhard Grill Ernst Meyer 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(11):3968-3972
Individual in situ polymerized fluorene chains 10–100 nm long linked by C–C bonds are pulled vertically from an Au(111) substrate by the tip of a low-temperature atomic force microscope. The conformation of the selected chains is imaged before and after manipulation using scanning tunneling microscopy. The measured force gradient shows strong and periodic variations that correspond to the step-by-step detachment of individual fluorene repeat units. These variations persist at constant intensity until the entire polymer is completely removed from the surface. Calculations based on an extended Frenkel–Kontorova model reproduce the periodicity and magnitude of these features and allow us to relate them to the detachment force and desorption energy of the repeat units. The adsorbed part of the polymer slides easily along the surface during the pulling process, leading to only small oscillations as a result of the high stiffness of the fluorenes and of their length mismatch with respect to the substrate surface structure. A significant lateral force also is caused by the sequential detachment of individual units. The gained insight into the molecule–surface interactions during sliding and pulling should aid the design of mechanoresponsive nanosystems and devices.Ever since the invention of the atomic force microscope (AFM) (1) and the first imaging applications, force spectroscopy has been applied to study the mechanical behavior of polymers (2); more complex chain-like biomolecules, e.g., DNA complementary strands (3); and proteins, subject to controlled extension (2) or applied force (4), mostly in solution and at room temperature. Reactive groups are chemically inserted at the ends and/or along each molecule to firmly bind some of them to suitably functionalized tips and sample surfaces. Irreversible jumps in curves of force vs. vertical separation may be associated in this way with the rupture of bonds or the unfolding of coiled subunits. If reproducible, the lowest peak in the histogram of the forces attained just before each jump is attributed to such an event in a single molecular chain or complementary pair. In the case of homogeneous polymers or protein segments, simulations based on two-state rate theory combined with a standard model of polymer nonlinear elasticity can reproduce such events, whereas reversible plateaus or continuous rises in the force may be associated with fast binding–rebinding processes or with large thermal fluctuations (2). Attention thus has focused on conformational changes strongly influenced by pulling speed or imposed force jumps (4) and also by external stimuli, e.g., optical excitation of inserted chromophores (5) or specific reactants or enzymes (6). Furthermore, mechanical forces recently were discovered by chemists as a unique stimulus to induce specific chemical reactions. In this so-called mechanochemistry, sonication typically is applied to polymer systems and is believed to result in a strong force acting on the weakest link in the chain, where the reaction takes place (7, 8). Regardless of the direct or indirect exposure to force, it is clear that the mechanics of polymer chains constrained in their surrounding environment is of utmost importance for a variety of biophysical and chemical processes as well as self-healing materials applications (9, 10).A few pulling studies have been conducted on polyelectrolytes unspecifically adsorbed on self-assembled monolayers via tunable electrostatic interactions (11), including DNA (12). They merely revealed noisy force plateaus, interpreted as continuous partial desorption of single chains, terminated by a drop to zero upon complete detachment from the surface. Despite the undisputed merit of these studies, little is known about the mechanical behavior of single molecular chains pulled off a surface, both defined and characterized on the atomic scale, in the absence of significant thermal fluctuations and drifts. Measurements at low temperature reduce the diffusion of adsorbates and provide an opportunity to determine the energetic landscape of specific molecules interacting with a surface under controlled conditions. As demonstrated here, the sliding and detachment mechanisms of individual polymer repeat units can then be inferred from the analysis of pulling experiments. A detailed interpretation of our results, based on a modified Frenkel–Kontorova (FK) model (13), also is presented. 相似文献
994.
Khan Hashim Ali Muhammad Mohsin Ansari Fawad Ali Shah Fakhar Ud Din Muhammad Abdul Basit 《Journal of microencapsulation》2019,36(1):10-20
The study was aimed to prepare a co-amorphous system of valsartan (VAL) with vanillin (VAN) for improving its solubility and dissolution followed by its confinement in mesoporous silica particles (MSPs) to stabilise the co-amorphous system and prevent its recrystallization. Amorphous VAL and VAN were obtained through quench-cooling and VAL/VAN binary co-amorphous system (VAL/VAN-CAS) was prepared through solvent evaporation technique. The particle size and morphology of VAL/VAN-CAS-MSPs were studied using scanning electron microscopy (SEM) and solid-state characterisation was performed by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The in vitro dissolution was investigated by dialysis bag diffusion method. SEM analysis revealed irregular shaped VAL/VAN-CAS-MSPs with a size range of 5–25?μm, while outcomes of DSC and XRPD confirmed the formation of VAL/VAN-CAS. The in vitro dissolution profiles demonstrated a significantly increased dissolution in first 60?minutes from VAL/VAN-CAS (~68%) and VAL/VAN-CAS-MSPs (~76%) compared to powder VAL (~25%). 相似文献
995.
996.
Ahlam Alhusaini Laila M. Fadda Hanaa M. Ali Iman H. Hasan Rehab A. Ali Enas A. Zakaria 《Pharmacological reports : PR》2019,71(6):1088-1094
BackgroundAcetamiprid (ACMP) is a member of the neonicotinoid group of insecticides. It is extensively used worldwide. The misuse of ACMP creates danger hazards to human and animal.MethodsACMP induced renal damage evidenced by an increase in kidney injury biomarkers. So the goal of this work is to clarify the reno protective effect of Quercetin (Qrctn) and/or Nano-glutathione (N-Gluta) solely or in combination to counterbalance the danger effect of ACMP. All treatments with the previous agents were coadministered orally with ACMP for one month.ResultsACMP ingestion caused a significant rise in serum creatinin, urea, and uric acid, TNF α along with renal cystatin C, lipid peroxidation and nitric oxide with the concomitant decline in the levels of reduced glutathione and IL-10 levels. Protein expression of ICAM was upregulated as well as mRNA expression of NF-κB while mRNA expression of Nrf2 was down-regulated. Immune histochemistry of TLR 4 revealed strong immune reaction. The administration of Qrctn or N-Gluta either individually or together modulated all the preceding aforementioned parameters.ConclusionFascinatingly Qrctn and N-Gluta combination was the most powerful regimen to frustrate ACMP reno-toxicity and may be deliberate as a hopeful applicant for renal therapy. 相似文献
997.
998.
Svenja Sydor Paul Manka Lea van Buren Sarah Theurer Suzan Schwertheim Jan Best Janette Heegsma Ali Saeed Diana Vetter Martin Schlattjan Anna Dittrich Maria I. Fiel Hideo A. Baba Alexander Dechêne Francisco J. Cubero Guido Gerken Ali Canbay Han Moshage Scott L. Friedman Klaas Nico Faber Lars P. Bechmann 《Liver international》2020,40(9):2172-2181
999.
Ernest Adeghate Mohamed Lotfy Crystal D'Souza Saleh Meqbel Alseiari Abdulla Ali Alsaadi Saif Abdo Qahtan 《Diabetes/metabolism research and reviews》2020,36(3)
The hypocretin/orexin (Hcrt/orexin) unit affects the functions of the nervous, cardiovascular, gastrointestinal, and reproductive systems. Hcrt/orexin ligands and receptors have been localized to different parts of the central and peripheral nervous systems, cerebrospinal fluid and blood, exocrine (pancreas, salivary, lacrimal) as well as endocrine (pancreatic islets, pituitary, adrenal) glands. Several factors including stress, glucagon‐like peptide‐1 agonists, glutamate, nicotine, glucose, and hypoglycaemia stimulate the expression of Hcrt/orexin system, but it is inhibited by ageing, bone morphogenetic protein, hypoxia/hypercapnia, melanocortin receptor accessory protein 2, and glucagon. Literature reports show that Hcrt/orexin can significantly increase insulin secretion from normal and diabetic rat pancreata. Hcrt/orexin decreases blood glucose concentration and reduces insulin resistance partly via increased tissue expression of glucose transporter type 4. It reduces obesity by increasing browning of fat cells and energy expenditure. Taken together, Hcrt/orexin modulates obesity and the metabolism of glucose and insulin. The Hcrt/orexin system may thus be a target in the development of new therapies for the treatment of diabetes mellitus. 相似文献