Integrated Biophysical Modeling of the SARS-CoV-2 Spike Protein Binding and Allosteric Interactions with Antibodies

Structural and biochemical studies of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 spike protein complexes with a panel of antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics and allosteric signaling in the spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters that enable a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. Coarse-grained and all-atom molecular dynamics simulations combined with mutational sensitivity mapping and perturbation-based profiling of the SARS-CoV-2 receptor-binding domain (RBD) complexes with CR3022 and CB6 antibodies enabled a detailed validation of the proposed approach and an extensive quantitative comparison with the experimental structural and deep mutagenesis scanning data. By combining in silico mutational scanning, perturbation-based modeling, and network analysis of the SARS-CoV-2 spike trimer complexes with H014, S309, S2M11, and S2E12 antibodies, we demonstrated that antibodies can incur specific and functionally relevant changes by modulating allosteric propensities and collective dynamics of the SARS-CoV-2 spike proteins. The results provide a novel insight into regulatory mechanisms of SARS-CoV-2 S proteins showing that antibody-escaping mutations can preferentially target structurally adaptable energy hotspots and allosteric effector centers that control functional movements and allosteric communication in the complexes

Two phase partitioning bioreactor applied to produced water treatment

Produced waters are the largest waste associated with the production of oil and gas; they contain dissolved salts, oil (dissolved and scattered organic compounds), chemicals and additives involved in the oil well operations, suspended particles, sand and other compounds, making their treatment very complex. In this paper, we propose the use of a TPPB (two phase partitioning bioreactor) for the biological treatment of produced waters. We model the application of the TPPB on the stream after classical pre-treatment stages: the reactor behaviour is based on the controlled release of substrate by means of an organic solvent. This study aims at developing a mathematical model for a TPPB adopting oleic alcohol (Adol 85 NF) as a solvent: we test model reliability by means of a sensitivity analysis in order to evaluate the reactor efficiency for chemical oxygen demand (COD) removal in a produced water stream, aimed at water reuse

Toward an efficient biorefining of microalgae and biomass alike. A unit operating view on how to mimick the optimisation history of the crude oil refining industry

One major hindrance to biomass deployment, and one which only benefitted from an unbalanced development, is refining into the different fractions which have a market value. Indeed, most products obtained from oil refining owe to the level of sophistication and optimisation reached by energy-integrated fractioning (mostly, distillation) networks. The separation stage of microalgal and lignocellulosic biomass could be addressed by using a converging approach employing a multipurpose solvent which may be adapted by one single and simple operation to different extractions. Such a single-solvent separation approach would lend itself to scaleup to a solvent-integrated fractionation network that might help mimicking the success story of the oil refining industry

Tacrolimus ointment in the management of atopic dermatitis

Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic inflammatory skin disease. AD long-term treatment is usually required to control and prevent flares, and patients need a treatment that is safe and efficacious when applied continuously or intermittently over a prolonged period of time. The treatment options should be chosen according to age, clinical features and severity of the disease in every single patient. For the treatment of a chronic disease like AD, sustained tolerability and efficacy of the applied medications are essential. A topical immunomodulator, tacrolimus ointment, provides an alternative to topical corticosteroids without the associated adverse events. Tacrolimus is a macrolide lactone with unique immunomodulatory properties and strong anti-inflammatory activities and can be used without increasing the risk of infection or other non-application site adverse events, and without loss of effectiveness, in patients with AD

Amino-functionalized poly(l-lactide) lamellar single crystals as a valuable substrate for delivery of HPV16-E7 tumor antigen in vaccine development

Background: Poly(L-lactide) (PLLA) is a biodegradable polymer currently used in many biomedical applications, including the production of resorbable surgical devices, porous scaffolds for tissue engineering, nanoparticles and microparticles for the controlled release of drugs or antigens. The surfaces of lamellar PLLA single crystals (PLLAsc) were provided with amino groups by reaction with a multifunctional amine and used to adsorb an Escherichia coli-produced human papillomavirus (HPV)16-E7 protein to evaluate its possible use in antigen delivery for vaccine development. Methods: PLLA single crystals were made to react with tetraethylenepentamine to obtain amino-functionalized PLLA single crystals (APLLAsc). Pristine and amino-functionalized PLLAsc showed a two-dimensional microsized and one-dimensional nanosized lamellar morphology, with a lateral dimension of about 15–20 µm, a thickness of about 12 nm, and a surface specific area of about 130 m2/g. Both particles were characterized and loaded with HPV16-E7 before being administered to C57BL/6 mice for immunogenicity studies. The E7-specific humoral-mediated and cell-mediated immune response as well as tumor protective immunity were analyzed in mice challenged with TC-1 cancer cells. Results: Pristine and amino-functionalized PLLAsc adsorbed similar amounts of E7 protein, but in protein-release experiments E7-PLLAsc released a higher amount of protein than E7-APLLAsc. When the complexes were dried for observation by scanning electron microscopy, both samples showed a compact layer, but E7-APLLAsc showed greater roughness than E7-PLLAsc. Immunization experiments in mice showed that E7-APLLAsc induced a stronger E7-specific immune response when compared with E7-PLLAsc. Immunoglobulin G isotyping and interferon gamma analysis suggested a mixed Th1/Th2 immune response in both E7-PLLAsc-immunized and E7-APLLAsc-immunized mice. However, only the mice receiving E7-APLLAsc were fully protected from TC-1 tumor growth after three doses of vaccine. Conclusion: Our results show that APLLA single crystals improve the immunogenicity of HPV16-E7 and indicate that E7-APLLAsc could be used for development of an HPV16 therapeutic vaccine against HPV16-related tumors

Mitochondrial cytochrome b DNA sequence variations: an approach to fish species identification in processed fish products.

The identification of fish species in food products is problematic because morphological features of the fish are partially or completely lost during processing. It is important to determine fish origin because of the increasing international seafood trade and because European Community Regulation 104/2000 requires that the products be labeled correctly. Sequence analysis of PCR products from a conserved region of the cytochrome b gene was used to identity fish species belonging to the families Gadidae and Merluccidae in 18 different processed fish products. This method allowed the identification of fish species in all samples. Fish in all of the examined products belonged to these two families, with the exception of one sample of smoked baccalà (salt cod), which was not included in the Gadidae cluster

David and Goliath: small banks in an era of consolidation. Evidence from Italy

Consolidation in the banking industry has caused concern about the survival of small banks. However, empirical evidence shows that often small banks are performing better than larger banks in terms of loan growth and profitability. This paper addresses the main question of “how David can be successful in a Goliath’s world” analysing two broad sets of issues, tested on a sample of Italian small banks. We first address the question of whether peculiarities of small banks, e.g their ability to lever on relationship lending, are good explanatory variables of their loan growth. Second, we investigate the relationship between loan growth and profitability and credit risk to point out which small banks can continue to be a viable competitor of larger bank

David and Goliath: small banks in an era of consolidation. Evidence from Italy

Consolidation in the banking industry has caused concern about the survival of small banks. However, empirical evidence shows that often small banks are performing better than larger banks in terms of loan growth and profitability. This paper addresses the main question of “how David can be successful in a Goliath’s world” analysing two broad sets of issues, tested on a sample of Italian small banks. We first address the question of whether peculiarities of small banks, e.g their ability to lever on relationship lending, are good explanatory variables of their loan growth. Second, we investigate the relationship between loan growth and profitability and credit risk to point out which small banks can continue to be a viable competitor of larger bank

The importance of sport activities to stimulate an educational management of students with SLD

In Italy, one student out of five, during his/her educational path from the early years of school up to University, faces difficulties in learning requiring the need of help by experts. This observation allows us affirming that, in Italian country, there are roughly 10 million students needing didactic support; among them, in particular, almost two million show the so-called Specific Learning Disorders (SLD). In this regard, this paper aims to identify and analyse a performing management strategy, in educational and social perspective, able to deal with the critical aspects relating to Specific Learning Disorders (SLD) in the main scholastic contexts such as School and University. Through a performance analysis of: data, laws and regulations, protocols of action and sources of literature, were detected a set of key determinants has been suggested to define and develop operational management solutions at different educational levels. An important result was that we identified in the sporting activity a tool of universal support able to achieve multiple benefits for supporting students with SLD. In fact, sport contributes significantly to the enhancement of the specific characteristics of these people, and the consequent increase in their self-esteem level and in their relational skills. This implies, in turn, a greater predisposition to school and university learning, favouring the overall development of the individual