Phylogenetically and antigenically distinct influenza A and B viruses (IAV and IBV) circulate in human populations, causing widespread morbidity. Antibodies (Abs) that bind epitopes conserved in both ...IAV and IBV hemagglutinins (HAs) could protect against disease by diverse virus subtypes. Only one reported HA Ab, isolated from a combinatorial display library, protects against both IAV and IBV. Thus, there has been so far no information on the likelihood of finding naturally occurring human Abs that bind HAs of diverse IAV subtypes and IBV lineages. We have now recovered from several unrelated human donors five clonal Abs that bind a conserved epitope preferentially exposed in the postfusion conformation of IAV and IVB HA2. These Abs lack neutralizing activity in vitro but in mice provide strong, IgG subtype-dependent protection against lethal IAV and IBV infections. Strategies to elicit similar Abs routinely might contribute to more effective influenza vaccines.
Abstract We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive ...treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1 -edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.
Immune memory of a first infection with influenza virus establishes a lasting imprint. Recall of that memory dominates the response to later infections or vaccinations by antigenically drifted ...strains. Early childhood immunization before infection may leave an imprint with different characteristics. We report here a comparison of imprinting by vaccination and infection in a small cohort of nonhuman primates (NHPs). We assayed serum antibody responses for binding with hemaglutinnins (HAs) both from the infecting or immunizing strain (H3 A/Aichi 02/1968) and from strains representing later H3 antigenic clusters ("forward breadth") and examined the effects of defined HA mutations on serum titers. Initial exposure by infection elicited strong HA-binding and neutralizing serum antibody responses but with little forward breadth; initial vaccination with HA from the same strain elicited a weaker response with little neutralizing activity but considerable breadth of binding, not only for later H3 HAs but also for HA of the 2009 H1 new pandemic virus. Memory imprinted by infection, reflected in the response to two immunizing boosts, was largely restricted (as in humans) to the outward-facing HA surface, the principal region of historical variation. Memory imprinted by immunization showed exposure to more widely distributed epitopes, including sites that have not varied during evolution of the H3 HA but that yield nonneutralizing responses. The mode of initial exposure thus affects both the strength of the response and the breadth of the imprint; design of next-generation vaccines will need to take the differences into account.
Context is a central construct in the study of performance appraisal (PA) systems, but to date studies linking the distal context within which organizations operate to PA have been limited in two ...ways. First, these studies have focused predominantly on national culture, and have paid less attention to the legal/political and economic environment within which organizations. Second, few studies reflect the growing international nature of business organizations, which create multiple layers of context (e.g., home and host country context). Drawing on both situational strength and institutional theories, we hypothesize the links between the “big three” facets of distal context (i.e., culture, legal/political, and economic) and the processes and purposes of PA systems. Using data from 472 multinational enterprises (MNEs) in 22 countries, we show that all three facets of the distal context of the host country influence decisions about the conduct of PA systems. In addition, we show that the culture and legal/political systems of the home country from which the MNE originated are also linked to the PA processes and purposes. Finally, we find evidence that MNEs are more likely to develop hybridized PA systems that depart from host country norms.
How Have Primate Lentiviruses Helped Us Better Understand Restriction Factors? Since the discoveries of HIV-1 and HIV-2 in humans and SIVmac in captive macaques, over 40 primate lentiviruses have ...been identified, all in African primates 7. ...comparative studies of the primate lentiviruses and their hosts can shed light on the evolutionary and biological significance of restriction. SIVmac arose by unintentional transmission of SIVsmm from African mangabeys to Asian macaques in captivity. Because of similarities to HIV infection and AIDS, SIV infection of macaques is a major animal model for AIDS research.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus macaques harbor three functionally distinct Trim5 alleles: Trim5α(Q) , Trim5α(TFP) and Trim5(CypA) . Despite the high degree ...of amino acid identity between Trim5α(Q) and Trim5α(TFP) alleles, the Q/TFP polymorphism results in the differential restriction of some primate lentiviruses, suggesting these alleles differ in how they engage these capsids. Simian immunodeficiency virus of rhesus macaques (SIVmac) evolved to resist all three alleles. Thus, SIVmac provides a unique opportunity to study a virus in the context of the Trim5 repertoire that drove its evolution in vivo. We exploited the evolved rhesus Trim5α resistance of this capsid to identify gain-of-sensitivity mutations that distinguish targets between the Trim5α(Q) and Trim5α(TFP) alleles. While both alleles recognize the capsid surface, Trim5α(Q) and Trim5α(TFP) alleles differed in their ability to restrict a panel of capsid chimeras and single amino acid substitutions. When mapped onto the structure of the SIVmac239 capsid N-terminal domain, single amino acid substitutions affecting both alleles mapped to the β-hairpin. Given that none of the substitutions affected Trim5α(Q) alone, and the fact that the β-hairpin is conserved among retroviral capsids, we propose that the β-hairpin is a molecular pattern widely exploited by Trim5α proteins. Mutations specifically affecting rhesus Trim5α(TFP) (without affecting Trim5α(Q) ) surround a site of conservation unique to primate lentiviruses, overlapping the CPSF6 binding site. We believe targeting this site is an evolutionary innovation driven specifically by the emergence of primate lentiviruses in Africa during the last 12 million years. This modularity in targeting may be a general feature of Trim5 evolution, permitting different regions of the PRYSPRY domain to evolve independent interactions with capsid.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In chronic lymphocytic leukemia (CLL), analysis of immunoglobulin heavy chain variable regions for somatic hypermutation identifies 2 prognostic subsets, mutated and unmutated. Investigators have ...postulated that unmutated and mutated CLL arises from malignant transformation of pre– and post–germinal center (GC) B cells, respectively. Alternatively, unmutated cases may arise from B cells stimulated by T-cell–independent antigens or from GC B cells with inactive somatic hypermutation. Activation-induced cytidine deaminase (AID), a protein essential for somatic hypermutation, is expressed by GC B cells in which this process occurs. We investigated AID mRNA expression in 20 CLL cases. In 8 cases we detected high expression of wild-type AID mRNA and 2 splice variants; in 12 cases and 5 normal peripheral blood B-cell samples we detected no expression using standard conditions. Of 8 CLL cases that highly expressed AID, 7 were unmutated, suggesting that this subset may arise from GC-experienced B cells with inactive somatic hypermutation, and may predict prognosis.
Background: This study evaluates and compares three-dimensional (3-D) changes in geometry of the first metatarsal (MT1) independent of soft tissue corrections of 5 common osteotomies: three distal ...(Chevron, Mitchell, and Wilson), one proximal (Stephens basal), and one combined proximal/distal (Scarf), using standardized synthetic bone models. Materials and Methods: A digitizing system was used to measure and record points on the synthetic bone models in 3-D space. Computer vector analysis calculated 3-D rotations and translations of the MT1 head plus the conventional intermetatarsal angle (IMA) and distal metatarsal articular angle (DMAA). Results: The Wilson and Mitchell's osteotomies produced significant shortening (p < 0.001) in contrast to the three other osteotomies. All the osteotomies produced a reduction in the 3-D IMA. The Scarf and Stephens basal osteotomies reduced the DMAA. All of the osteotomies resulted in lateral translations and depression of the MT1 head. While there were no significant (p > 0.05) translational differences between the Scarf and Stephens basal osteotomies, there were rotational differences, with the Stephens basal producing significantly more plantar flexion (p = 0.000) and pronation (p < 0.001) than the Scarf. Conclusion: This geometric study indicated many of the MT1 head changes following metatarsal osteotomy to be out-of-plane translational and multiplanar rotations which cannot be determined using AP radiographs alone. Clinical Relevance: We advocate judicious choice of osteotomy to achieve the desired correction of hallux valgus in each individual.
How Have Primate Lentiviruses Helped Us Better Understand Restriction Factors? Since the discoveries of HIV-1 and HIV-2 in humans and SIVmac in captive macaques, over 40 primate lentiviruses have ...been identified, all in African primates 7. ...comparative studies of the primate lentiviruses and their hosts can shed light on the evolutionary and biological significance of restriction. SIVmac arose by unintentional transmission of SIVsmm from African mangabeys to Asian macaques in captivity. Because of similarities to HIV infection and AIDS, SIV infection of macaques is a major animal model for AIDS research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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