VLP-Based COVID-19 Vaccines: An Adaptable Technology against the Threat of New Variants.

Virus-like particles (VLPs) are a versatile, safe, and highly immunogenic vaccine platform. Recently, there are developmental vaccines targeting SARS-CoV-2, the causative agent of COVID-19. The COVID-19 pandemic affected humanity worldwide, bringing out incomputable human and financial losses. The race for better, more efficacious vaccines is happening almost simultaneously as the virus increasingly produces variants of concern (VOCs). The VOCs Alpha, Beta, Gamma, and Delta share common mutations mainly in the spike receptor-binding domain (RBD), demonstrating convergent evolution, associated with increased transmissibility and immune evasion. Thus, the identification and understanding of these mutations is crucial for the production of new, optimized vaccines. The use of a very flexible vaccine platform in COVID-19 vaccine development is an important feature that cannot be ignored. Incorporating the spike protein and its variations into VLP vaccines is a desirable strategy as the morphology and size of VLPs allows for better presentation of several different antigens. Furthermore, VLPs elicit robust humoral and cellular immune responses, which are safe, and have been studied not only against SARS-CoV-2 but against other coronaviruses as well. Here, we describe the recent advances and improvements in vaccine development using VLP technology

Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2020-05-20T13:36:52Z No. of bitstreams: 2 Orge Yasmin Diniz , Phenotype....pdf: 16650804 bytes, checksum: c3eb41edf819fec369deb1d2cfc161da (MD5) Orge Yasmin Diniz , Phenotype....pdf: 16650804 bytes, checksum: c3eb41edf819fec369deb1d2cfc161da (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2020-05-20T14:09:16Z (GMT) No. of bitstreams: 2 Orge Yasmin Diniz , Phenotype....pdf: 16650804 bytes, checksum: c3eb41edf819fec369deb1d2cfc161da (MD5) Orge Yasmin Diniz , Phenotype....pdf: 16650804 bytes, checksum: c3eb41edf819fec369deb1d2cfc161da (MD5)Made available in DSpace on 2020-05-20T14:09:16Z (GMT). No. of bitstreams: 2 Orge Yasmin Diniz , Phenotype....pdf: 16650804 bytes, checksum: c3eb41edf819fec369deb1d2cfc161da (MD5) Orge Yasmin Diniz , Phenotype....pdf: 16650804 bytes, checksum: c3eb41edf819fec369deb1d2cfc161da (MD5) Previous issue date: 2020Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil.MRC Centre for Regenerative Medicine. Edinburgh, UK.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil / D’Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil.Universidade Federal da Bahia. Institute of Health Sciences. Salvador, BA, Brasil.MRC Centre for Regenerative Medicine. Edinburgh, UK.São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil / D’Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil.São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil / D’Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / National Institute of Science and Technology for Regenerative Medicine. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil.MRC Centre for Regenerative Medicine. Edinburgh, UK.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / National Institute of Science and Technology for Regenerative Medicine. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil / D’Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil / National Institute of Science and Technology for Regenerative Medicine. Rio de Janeiro, RJ, Brazil /Hepatocyte-like cells (iHEPs) generated by transcription factor-mediated direct reprogramming of somatic cells have been studied as potential cell sources for the development of novel therapies targeting liver diseases. The mechanisms involved in direct reprogramming, stability after long-term in vitro expansion, and safety profile of reprogrammed cells in different experimental models, however, still require further investigation. Methods: iHEPs were generated by forced expression of Foxa2/Hnf4a in mouse mesenchymal stromal cells and characterized their phenotype stability by in vitro and in vivo analyses. Results: The iHEPs expressed mixed hepatocyte and liver progenitor cell markers, were highly proliferative, and presented metabolic activities in functional assays. A progressive loss of hepatic phenotype, however, was observed after several passages, leading to an increase in alpha-SMA+ fibroblast-like cells, which could be distinguished and sorted from iHEPs by differential mitochondrial content. The resulting purified iHEPs proliferated, maintained liver progenitor cell markers, and, upon stimulation with lineage maturation media, increased expression of either biliary or hepatocyte markers. In vivo functionality was assessed in independent pre-clinical mouse models. Minimal engraftment was observed following transplantation in mice with acute acetaminophen-induced liver injury. In contrast, upon transplantation in a transgenic mouse model presenting host hepatocyte senescence, widespread engraftment and uncontrolled proliferation of iHEPs was observed, forming islands of epithelial-like cells, adipocytelike cells, or cells presenting both morphologies. Conclusion: The results have significant implications for cell reprogramming, suggesting that iHEPs generated by Foxa2/Hnf4a expression have an unstable phenotype and depend on transgene expression for maintenance of hepatocyte-like characteristics, showing a tendency to return to the mesenchymal phenotype of origin and a compromised safety profil

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

Landscape determinants of European roller foraging habitat: implications for the definition of agri-environmental measures for species conservation

Across much of Europe, farmland birds are declining more than those in other habitats. From a conservation perspective, identifying the primary preferred habitats could help improve the foraging conditions of target species and, consequently, enhance their breeding success and survival. Here, we investigated the ranging behaviour and foraging habitat selection of the European roller (Coracias garrulus) during the breeding season in an agricultural landscape of South Iberia. The occurrence of foraging rollers was predicted to gradually increase with decreasing distance from the nest and increasing availability of perches, such as fences and electric wires. Traditional olive groves and stubble fields were positively and negatively associated with the occurrence of rollers, respectively. Additionally, analysis of hunting strikes showed that rollers highly prefer foraging in fallows rather than cereal or stubble fields. Prey surveys revealed that fallows had the highest abundance of grasshoppers, rollers’ preferred prey during chick-rearing. Pair home-ranges, obtained from 95% fixed Kernel estimators averaged 70.9 ha (range = 34–118 ha) and most foraging trips (80%) occurred in the close vicinity of the nest (<500 m). Number of chicks fledged was not affected by mean foraging distances travelled during the chick-rearing period. Overall, our results suggest that traditional extensive practices of cereal cultivation, with large areas of low-intensity grazed fallows, represent a high-quality foraging habitat for rollers and should be promoted through agri-environmental schemes within at least 1-km radius from the nest. These recommendations are targeted at the roller, but have been shown to apply broadly to several other steppe-bird species

Possible failure of novel direct-acting oral anticoagulants in management of pulmonary embolism: a case report

BACKGROUND: The relative effectiveness of vitamin K antagonists compared with novel oral anticoagulants in treating pulmonary embolism remains unclear. Recent trials comparing the efficacy of vitamin K antagonists with factor Xa inhibitors for the treatment of pulmonary emboli have been non-inferiority studies based primarily on risk reduction (such as bleeding events), rather than resolution of specific diseases such as pulmonary embolism. Consequently, there is a lack of evidence indicating which of these agents are more effective. Here, we present a case where pulmonary emboli were treated with novel oral anticoagulants followed by warfarin to discuss the potential limitations in the use of novel oral anticoagulants as prevention or treatment of thromboembolism and the continued role for warfarin in this setting. CASE PRESENTATION: A 34-year-old African American woman presented to our clinic with shortness of breath and pleuritic chest pain several months post-surgery. She was identified as having multiple bilateral pulmonary embolisms and was treated with several novel oral anticoagulants, which failed to resolve the clots. Complete resolution was achieved upon switching to warfarin. CONCLUSIONS: The patient described in this report failed to respond to novel oral anticoagulant therapy, but her emboli resolved when she was treated with warfarin. This study challenges the notion that factor Xa inhibitors are better alternatives to vitamin K anticoagulants in the treatment of pulmonary emboli based on their safety profile and ease of use alone. As a result, further post-marketing investigations into the efficacy of these agents in the management of pulmonary emboli may be warranted

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6 pmol min−1 mg−1. The Km of the tumoral enzyme (42±8 μM) is similar to that in healthy colorectal epithelium (36±8 μM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2 pmol min−1 mg−1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs

Leishmania donovani: Immunostimulatory Cellular Responses of Membrane and Soluble Protein Fractions of Splenic Amastigotes in Cured Patient and Hamsters

Visceral leishmaniasis (VL), caused by the intracellular parasite Leishmania donovani, L. chagasi and L. infantum is characterized by defective cell-mediated immunity (CMI) and is usually fatal if not treated properly. An estimated 350 million people worldwide are at risk of acquiring infection with Leishmania parasites with approximately 500,000 cases of VL being reported each year. In the absence of an efficient and cost-effective antileishmanial drug, development of an appropriate long-lasting vaccine against VL is the need of the day. In VL, the development of a CMI, capable of mounting Th1-type of immune responses, play an important role as it correlate with recovery from and resistance to disease. Resolution of infection results in lifelong immunity against the disease which indicates towards the feasibility of a vaccine against the disease. Most of the vaccination studies in Leishmaniasis have been focused on promastigote- an infective stage of parasite with less exploration of pathogenic amastigote form, due to the cumbersome process of its purified isolation. In the present study, we have isolated and purified splenic amastigotes of L. donovani, following the traditional protocol with slight modification. These were fractionated into five membranous and soluble subfractions each i.e MAF1-5 and SAF1-5 and were subjected for evaluation of their ability to induce cellular responses. Out of five sub-fractions from each of membrane and soluble, only four viz. MAF2, MAF3, SAF2 and SAF3 were observed to stimulate remarkable lymphoproliferative, IFN-γ, IL-12 responses and Nitric Oxide production, in Leishmania-infected cured/exposed patients and hamsters. Results suggest the presence of Th-1 type immunostimulatory molecules in these sub-fractions which may further be exploited for developing a successful subunit vaccine from the less explored pathogenic stage against VL

A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks

Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson-Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP

High-growth firms and productivity:evidence from the United Kingdom

Abstract There is considerable evidence that high-growth firms (HGFs) contribute significantly to employment and economic growth. However, the literature so far does not adequately explore the link between HGFs and productivity. This paper investigates the empirical link between total factor productivity (TFP) growth and HGFs, defined in terms of sales growth, in the United Kingdom over the period 2001-2010, by examining two related research questions. Firstly, does higher TFP growth lead to HGF status and secondly, does HGF experience help firms achieve faster TFP growth? Our findings reveal that firms in both the manufacturing and services sectors are more likely to become HGFs when they exhibit higher TFP growth. In addition, firms that have had HGF experience tend to enjoy faster TFP growth following the high-growth episodes. Policy implications are drawn based on the self-reinforcing process of the high-growth phenomenon that is revealed by our results

The global pendulum swing towards community health workers in low- and middle-income countries: A scoping review of trends, geographical distribution and programmatic orientations, 2005 to 2014

BACKGROUND: There has been a substantial increase in publications and interest in community health workers (CHWs) in low- and middle-income countries (LMIC) over the last years. This paper examines the growth, geographical distribution and programmatic orientations of the indexed literature on CHWs in LMIC over a 10-year period. METHODS: A scoping review of publications on CHWs from 2005 to 2014 was conducted. Using an inclusive list of terms, we searched seven databases (including MEDLINE, CINAHL, Cochrane) for all English-language publications on CHWs in LMIC. Two authors independently screened titles/abstracts, downloading full-text publications meeting inclusion criteria. These were coded in an Excel spreadsheet by year, type of publication (e.g. review, empirical), country, region, programmatic orientation (e.g. maternal-child health, HIV/AIDS, comprehensive) and CHW roles (e.g. prevention, treatment) and further analysed in Stata14. Drawing principally on the subset of review articles, specific roles within programme areas were identified and grouped. FINDINGS: Six hundred seventy-eight publications from 46 countries on CHWs were inventoried over the 10-year period. There was a sevenfold increase in annual number of publications from 23 in 2005 to 156 in 2014. Half the publications were reporting on initiatives in Africa, a third from Asia and 11 % from the Americas (mostly Brazil). The largest single focus and driver of the growth in publications was on CHW roles in meeting the Millennium Development Goals of maternal, child and neonatal survival (35 % of total), followed by HIV/AIDS (16 %), reproductive health (6 %), non-communicable diseases (4 %) and mental health (4 %). Only 17 % of the publications approached CHW roles in an integrated fashion. There were also distinct regional (and sometimes country) profiles, reflecting different histories and programme traditions. CONCLUSIONS: The growth in literature on CHWs provides empirical evidence of ever-increasing expectations for addressing health burdens through community-based action. This literature has a strong disease- or programme-specific orientation, raising important questions for the design and sustainable delivery of integrated national programmes.Scopu