Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice

Protection against SARS-CoV-2 and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor-binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2–RBD-nanoparticles or COVID-19 convalescent human plasmas. Moreover, sera from mosaic-RBD–immunized mice neutralized heterologous pseudotyped coronaviruses equivalently or better after priming than sera from homotypic SARS-CoV-2–RBD-nanoparticle immunizations, demonstrating no immunogenicity loss against particular RBDs resulting from co-display. A single immunization with mosaic-RBD-nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Many anti-SARS-CoV-2 neutralizing antibodies target the ACE2-binding site on viral spike receptor-binding domains (RBDs). The most potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly-emergent zoonotic sarbecoviruses and variants, but usually show only weak neutralization potencies. We characterized two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibited broad recognition and potent neutralization of zoonotic coronavirus and SARS-CoV-2 variants. C118-RBD and C022-RBD structures revealed CDRH3 mainchain H-bond interactions that extended an RBD β-sheet, thus reducing sensitivity to RBD sidechain changes, and epitopes that extended from the cryptic epitope to occlude ACE2 binding. A C118-spike trimer structure revealed rotated RBDs to allow cryptic epitope access and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics

Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires

Female high heel shoes: a study of comfort

Protection was the basic principle underlying the creation of footwear, once humankind felt the need to protect feet from direct contact with soil, heat, cold and sharp objects. However, this accessory soon acquired cultural, aesthetic, symbolic significance, and apparently it was not related to comfort. This work aims to analyze comfort in women footwear, especially high heels shoe. We intended to understand the emotional relationship of consumers with this type of accessory, as well as to understand to what extent women are willing to give up comfort in favor of aesthetics. For this purpose, a questionnaire was designed, aimed at the female audience in order to understand the relevance of women's footwear, their daily relationship with shoes, the specificity of heels and the problems caused by it.This work is supported by FEDER funds through the Competitivity Factors Operational Programme - COMPETE and by national funds through FCT – Foundation for Science and Technology within the scope of the project POCI-01-0145-FEDER-007136info:eu-repo/semantics/publishedVersio

Number of People Blind or Visually Impaired by Glaucoma Worldwide and in World Regions 1990 – 2010: A Meta-Analysis

Objective: To assess the number of individuals visually impaired or blind due to glaucoma and to examine regional differences and temporal changes in this parameter for the period from 1990 to 2012. Methods: As part of the Global Burden of Diseases (GBD) Study 2010, we performed a systematic literature review for the period from 1980 to 2012. We primarily identified 14,908 relevant manuscripts, out of which 243 high-quality, population-based studies remained after review by an expert panel that involved application of selection criteria that dwelt on population representativeness and clarity of visual acuity methods used. Sixty-six specified the proportion attributable to glaucoma. The software tool DisMod-MR (Disease Modeling–Metaregression) of the GBD was used to calculate fraction of vision impairment due to glaucoma. Results: In 2010, 2.1 million (95% Uncertainty Interval (UI):1.9,2.6) people were blind, and 4.2 (95% UI:3.7,5.8) million were visually impaired due to glaucoma. Glaucoma caused worldwide 6.6% (95% UI:5.9,7.9) of all blindness in 2010 and 2.2% (95% UI:2.0,2.8) of all moderate and severe visual impairment (MSVI). These figures were lower in regions with younger populations (10%). From 1990 to 2010, the number of blind or visually impaired due to glaucoma increased by 0.8 million (95%UI:0.7, 1.1) or 62% and by 2.3 million (95%UI:2.1,3.5) or 83%, respectively. Percentage of global blindness caused by glaucoma increased between 1990 and 2010 from 4.4% (4.0,5.1) to 6.6%. Age-standardized prevalence of glaucoma related blindness and MSVI did not differ markedly between world regions nor between women. Significance: By 2010, one out of 15 blind people was blind due to glaucoma, and one of 45 visually impaired people was visually impaired, highlighting the increasing global burden of glaucoma

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon α2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier “Asian-Pacific consensus statement on the management of chronic hepatitis B” was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included