Fast de novo antibody structure prediction with atomic accuracy

Background: In the field of antibody engineering, an essential task is to design a novel antibody whose paratopes bind to a specific antigen with correct epitopes. Understanding antibody structure and its paratope can facilitate a mechanistic understanding of its function. Therefore, antibody structure prediction from its sequence alone has always been a highly valuable problem for de novo antibody design. AlphaFold2 (AF2), a breakthrough in the field of structural biology, provides a solution to this protein structure prediction problem by learning a deep learning model. However, the computational efficiency and undesirable prediction accuracy on antibody, especially on the complementarity-determining regions limit its applications in de novo antibody design. Method(s): To learn informative representation of antibodies, we trained a deep antibody language model (ALM) on curated sequences from observed antibody space database via a well-designed transformer model. We also developed a novel model named xTrimoABFold++ to predict antibody structure from antibody sequence only based on the pretrained ALM as well as efficient evoformers and structural modules. The model was trained end-to-end on the antibody structures in PDB by minimizing the ensemble loss of domain-specific focal loss on CDR and the frame aligned point loss. Result(s): xTrimoABFold++ outperforms AF2 and OmegaFold, HelixFold-Single with 30+% improvement on RMSD. Also, it is 151 times faster than AF2 and predicts antibody structure in atomic accuracy within 20 seconds. In recently released antibodies, for example, cemiplimab of PD1 (PDB: 7WVM) and cross-neutralizing antibody 6D6 of SARS-CoV-2 (PDB: 7EAN), the RMSD of xTrimoABFold++ are 0.344 and 0.389 respectively. Conclusion(s): To the best of our knowledge, xTrimoABFold++ achieved the state-of-the-art in antibody structure prediction. Its improvement on both accuracy and efficiency makes it a valuable tool for de novo antibody design, and could make further improvement in immuno-theory.

The Politics of Intersecting Crises: The Effect of the COVID-19 Pandemic on Climate Policy Preferences

Few contemporary crises have reshaped public policy as dramatically as the COVID-19 pandemic. In its shadow, policymakers have debated whether other pressing crises—including climate change—should be integrated into COVID-19 policy responses. Public support for such an approach is unclear: the COVID-19 crisis might eclipse public concern for other policy problems, or complementarities between COVID-19 and other issues could boost support for broad government interventions. In this research note, we use a conjoint experiment, panel study, and framing experiment to assess the substitutability or complementarity of COVID-19 and climate change among US and Canadian publics. We find no evidence that the COVID-19 crisis crowds out public concern about the climate crisis. Instead, we find that the publics in both countries prefer that their governments integrate climate action into COVID-19 responses. We also find evidence that analogizing climate change with COVID-19 may increase concern about climate change.

Efectos económicos de la complementariedad comercial en la negociación de un tratado de libre comercio entre México y Corea del Sur *

México y Corea del Sur han avanzado en sus vínculos comerciales desde que iniciaron relaciones diplomáticas en 1962. Actualmente, los gobiernos de ambas economías se encuentran discutiendo la posibilidad de negociar un acuerdo de libre comercio. El objetivo de esta investigación es evaluar los efectos potenciales de dicho acuerdo. Para ello, se utilizan índices de intensidad comercial, ventajas comparativas reveladas, complementariedad y similitud comercial. Los resultados obtenidos muestran que los dos países han visto intensificar sus relaciones comerciales, lo que ha convertido a México en el principal socio comercial de Corea del Sur en América Latina, y ha dado lugar a una estructura comercial de complementariedad con ventajas para México en el comercio de combustibles minerales, lubricantes, maquinaria y equipo de transporte. También se obtuvo evidencia de la existencia de una asimetría en sus tarifas arancelarias que podría generar ventajas comerciales, sobre todo para México en el sector primario, en caso de lograr avanzar a la firma de un tratado de libre comercio.Alternate :Mexico and South Korea have progressed in their commercial affairs since they began diplomatic relations in 1962. Currently, the possibility of negotiating a free trade agreement between both economies is being raised. The objective of this research is to evaluate the potential effects of such a trade agreement for both countries. For this, indexes of commercial intensity, revealed comparative advantages, complementarity, and commercial similarity are used. The results show that these two countries have intensified their trade relations, turning Mexico into South Korea's main trading partner in Latin America and giving rise to a complementary trade structure with advantages for Mexico in the trade of mineral fuels, lubricants, machinery, and transport equipment. Also, an asymmetry was found in the tariff rates that could generate commercial advantages, especially for Mexico in the primary sector in case of the signing of a free trade agreement.

A potential antibody repertoire diversification mechanism through tyrosine sulfation for biotherapeutics engineering and production.

The diversity of three hypervariable loops in antibody heavy chain and light chain, termed the complementarity-determining regions (CDRs), defines antibody's binding affinity and specificity owing to the direct contact between the CDRs and antigens. These CDR regions typically contain tyrosine (Tyr) residues that are known to engage in both nonpolar and pi stacking interaction with antigens through their complementary aromatic ring side chains. Nearly two decades ago, sulfotyrosine residue (sTyr), a negatively charged Tyr formed by Golgi-localized membrane-bound tyrosylprotein sulfotransferases during protein trafficking, were also found in the CDR regions and shown to play an important role in modulating antibody-antigen interaction. This breakthrough finding demonstrated that antibody repertoire could be further diversified through post-translational modifications, in addition to the conventional genetic recombination. This review article summarizes the current advances in the understanding of the Tyr-sulfation modification mechanism and its application in potentiating protein-protein interaction for antibody engineering and production. Challenges and opportunities are also discussed.

Assessing the effects of trade regionalism in East Asia – evidence from augmented gravity models

This paper investigates the effects of trade regionalism in East Asia from 1995 to 2018, by applying a series of gravity models. An initial, basic gravity model is repeatedly augmented to account for a range of economic, geographical, cultural, and above all institutional factors representing free trade agreements in effect. Unlike previous studies, this investigation distinguishes between the bilateral and multilateral measures of regional trading arrangements. Two interesting findings are reported. First, the results confirm the impact of trade regionalism on the export flows between the economies of East Asia in the period under study. Second, the effects of multilateral trading agreements vary greatly depending on the agreement and on the particular country's range of influence, in particular cases showing no sufficient economic benefits. Overall, the results point to the complementarity of bilateral and multilateral trading arrangements in the region and to the emergence of a certain distinctive model of cooperation and integration in East Asia – which has been underpinned during the COVID-19 pandemic by the conclusion of the Regional Comprehensive Economic Partnership (RCEP), and which will be further verified in the post-COVID character of global trade and regional trading arrangements.

T Cell Receptor Sequences Amplified during Severe COVID-19 and Multisystem Inflammatory Syndrome in Children Mimic SARS-CoV-2, Its Bacterial Co-Infections and Host Autoantigens.

Published hypervariable region V-beta T cell receptor (TCR) sequences were collected from people with severe COVID-19 characterized by having various autoimmune complications, including blood coagulopathies and cardiac autoimmunity, as well as from patients diagnosed with the Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C). These were compared with comparable published v-beta TCR sequences from people diagnosed with KD and from healthy individuals. Since TCR V-beta sequences are supposed to be complementary to antigens that induce clonal expansion, it was surprising that only a quarter of the TCR sequences derived from severe COVID-19 and MIS-C patients mimicked SARS-CoV-2 proteins. Thirty percent of the KD-derived TCR mimicked coronaviruses other than SARS-CoV-2. In contrast, only three percent of the TCR sequences from healthy individuals and those diagnosed with autoimmune myocarditis displayed similarities to any coronavirus. In each disease, significant increases were found in the amount of TCRs from healthy individuals mimicking specific bacterial co-infections (especially Enterococcus faecium, Staphylococcal and Streptococcal antigens) and host autoantigens targeted by autoimmune diseases (especially myosin, collagen, phospholipid-associated proteins, and blood coagulation proteins). Theoretical explanations for these surprising observations and implications to unravel the causes of autoimmune diseases are explored.

Resource integration capabilities to enable platform complementarity in healthcare service ecosystem co-creation

Purpose Covid has increased the usage of multisided digital platforms. For companies, this has become a business opportunity. Data usage on platforms requires that platform companies co-create services for common customers. In this case, the target is not to make the same value proposition but rather to use the resources such as data, knowledge, technology, or institutions in a complementary manner. Platforms are characterized as a combination of hardware and software including standards, interfaces, and rules making it possible for different ecosystem players to complement and interact in the ecosystem. Current ecosystems include several platforms that do not work without resource integration. The purpose of this study is to increase understanding what do we mean by resource complementarity in service ecosystems. Design/methodology/approach This study was done via an in-depth qualitative case study in which a health service ecosystem co-creating technological surgery innovation was used as a unit of analysis. Findings The authors' findings suggest that key resource capabilities, to enable complementarity in service ecosystems, are motivation, knowledge, skills, data and complementary designed technology components. Research limitations/implications The authors' study increases theoretical understanding of what does one mean by construct of resource complementarity. Practical implications From a managerial perspective, it is shown that organizations need to develop adaptive capabilities to utilize internal and external competencies and resources and enable co-creative processes within the service ecosystem. Originality/value Very few empirical studies in the marketing literature have focused on multi-sided digital platforms and their resource complementarity in the data-driven healthcare ecosystem settings.

Complementary Sets of Autoantibodies Induced by SARS-CoV-2, Adenovirus and Bacterial Antigens Cross-React with Human Blood Protein Antigens in COVID-19 Coagulopathies.

COVID-19 patients often develop coagulopathies including microclotting, thrombotic strokes or thrombocytopenia. Autoantibodies are present against blood-related proteins including cardiolipin (CL), serum albumin (SA), platelet factor 4 (PF4), beta 2 glycoprotein 1 (ß2GPI), phosphodiesterases (PDE), and coagulation factors such as Factor II, IX, X and von Willebrand factor (vWF). Different combinations of autoantibodies associate with different coagulopathies. Previous research revealed similarities between proteins with blood clotting functions and SARS-CoV-2 proteins, adenovirus, and bacterial proteins associated with moderate-to-severe COVID-19 infections. This study investigated whether polyclonal antibodies (mainly goat and rabbit) against these viruses and bacteria recognize human blood-related proteins. Antibodies against SARS-CoV-2 and adenovirus recognized vWF, PDE and PF4 and SARS-CoV-2 antibodies also recognized additional antigens. Most bacterial antibodies tested (group A streptococci [GAS], staphylococci, Escherichia coli [E. coli], Klebsiella pneumoniae, Clostridia, and Mycobacterium tuberculosis) cross-reacted with CL and PF4. while GAS antibodies also bound to F2, Factor VIII, Factor IX, and vWF, and E. coli antibodies to PDE. All cross-reactive interactions involved antibody-antigen binding constants smaller than 100 nM. Since most COVID-19 coagulopathy patients display autoantibodies against vWF, PDE and PF4 along with CL, combinations of viral and bacterial infections appear to be necessary to initiate their autoimmune coagulopathies.

What Does Comparative Policy Analysis Have to Do with the Structure, Institution and Agency Debate?

A growing number of political and policy scientists have utilized institutional theory to explain how the purposeful actions of agents shape and are shaped by structural, institutional, and agential factors. Most current studies, however, have conflated and/or combined the fundamental concepts of structure, institution, and actor, overlooking how their interactions shape policy and institutional outcomes. Furthermore, such research lacks an approach that allows a more comprehensive means to integrate the various dimensions of such interactions. By studying these distinct but interdependent causal factors through an integrative approach, we provide a richer, more comprehensive understanding of contingent conditions, agency, and outcomes.

Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses.

With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emergent human virus since December 2019, the world population is susceptible to coronavirus disease 2019 (COVID-19). SARS-CoV-2 has higher transmissibility than the previous coronaviruses, associated by the ribonucleic acid (RNA) virus nature with high mutation rate, caused SARS-CoV-2 variants to arise while circulating worldwide. Neutralizing antibodies are identified as immediate and direct-acting therapeutic against COVID-19. Single-domain antibodies (sdAbs), as small biomolecules with non-complex structure and intrinsic stability, can acquire antigen-binding capabilities comparable to conventional antibodies, which serve as an attractive neutralizing solution. SARS-CoV-2 spike protein attaches to human angiotensin-converting enzyme 2 (ACE2) receptor on lung epithelial cells to initiate viral infection, serves as potential therapeutic target. sdAbs have shown broad neutralization towards SARS-CoV-2 with various mutations, effectively stop and prevent infection while efficiently block mutational escape. In addition, sdAbs can be developed into multivalent antibodies or inhaled biotherapeutics against COVID-19.

Toward a fractalomic idiotype/anti-idiotypic paradigm.

The CoViD-19 pandemic has demonstrated the need for future developments in anti-viral immunology. We propose that artificial intelligence (AI) and machine learning, and in particular fractal analysis could play a crucial role in that context. Fractals - never-ending repeats of self-similar shapes whose composite tend to resemble the whole - are found in most natural biological structures including immunoglobulin and antigenic epitopes. Increased knowledge of the fractalomic properties of the idiotype/anti-idiotypic paradigm should help develop a novel and improved simplified artificial model of the immune system. Case in point, the regulation and dampening of antibodies as well as the synergetic recognition of an antigen by multiple idiotypes are both immune mechanisms that require further analysis. An enhanced understanding of these complexities could lead to better data analysis for novel vaccines to improve their sensitivity and specificity as well as open other new doors in the field of immunology.

How Will In-Person and Online Grocery Shopping and Meal Consumption Activities Evolve After COVID-19?

COVID-19 has drastically altered the daily lives of many people, forcing them to spend more time at home. This shift significantly increased online grocery shopping and ordering for food while restrictions and social distancing measures were in place. As re-opening begins, little is known about the way virtual and in-person shopping/eating activities will evolve after the pandemic. This study adopts a multivariate ordered probit model to investigate individuals' preferences toward the following activities after the pandemic: online grocery shopping, in-store grocery shopping, online ordering of food, and eating-out at restaurants. The model retained statistically significant error correlations among the activities, confirming the need for joint modeling. Model results suggested that individuals with lower income and with children are likely to perform grocery shopping and eating-out activities in person. Individuals owning a vehicle and a driver's license have a higher likelihood of less frequent online shopping and more frequent in-store grocery shopping. Individuals with transit passes prefer to order groceries online and engage in eat-out activities frequently. Individuals residing in mixed land use areas prefer frequent in-store grocery shopping whereas suburban dwellers prefer it less frequently. The model confirms complementarity and substitution effects. For instance, online food ordering revealed a complementary effect on eating-out activities whereas online grocery shopping confirmed a substitution effect on in-store grocery shopping. These findings provide important behavioral insights into travel activity patterns in the post-pandemic era, which will help in understanding the inter-relationships between online and in-person shopping/eating activities, and accommodating such inter-dependencies within the travel demand forecasting models for effective policy-making.

Cucumis melo var. momordica as a Potent Antidiabetic, Antioxidant and Possible Anticovid Alternative: Investigation through Experimental and Computational Methods.

Diabetes mellitus is a typical life threatening of disease, which generate due to the dysfunction of ß cells of pancreas. In 2014, WHO stated that 422 million people were infected with DM. The current pattern of management of diabetes included synthetic or plant based oral hypoglycemic drugs and insulin but drug resentence is become a very big issues in antidiabetic therapy. Thus, it's very earnest to discover now medication for this disease. Now the days, it is well acknowledged that diabetic patients are more prone towards covid and related complications. Thus, medical practitioners reformed the methodology of prescribing medication for covid infected antidiabetic therapy and encouraging the medication contains dual pharmacological properties. It is also well know that polyphenols specifically hold a significant role in oxidative stress and reduced the severity of many inflammatory diseases. Cucumis melo has rich history as ethano-pharmacological use in Indian subcontinent. The fruit and seed are well-known for the treatment of various diseases due to the presence of phenolics. Therefore, in this study, the combined mixture of flower and seeds were used for the extraction of polyphenolic rich extract and tested for antidiabetic activity through the antioxidant and in vivo experiments. The antioxidant potential measurement exhibited that the selected plant extract has the significant competence to down-regulate oxidative stress (DPPH scavenging IC50 at 60.7±1.05 µg/mL, ABTS IC50 at 62.15±0.50 µg/mL). Furthermore, the major polyphenolic phyto-compounds derived from the Cucumis melo were used for in silico anticovid activity, docking, and complementarity studies. The anticovid activity prognosis reflected that selected phyto-compounds amentoflavone and vanillic acid have optimal possibility to interact with 3C-like protease and through this moderate anticovid activity can be exhibit. The docking experiments established that the selected compounds have propensity to interact with protein tyrosine phosphatase 1B, 11ß-Hydroxysteroid dehydrogenase, superoxide dismutase, glutathione peroxidase, and catalase ß-glucuronidase receptor. In vivo experiments showed that 500 mg/kg, Cucumis melo extract ominously amplified body weight, plasma insulin, high-density lipoprotein levels, and biochemical markers. Furthermore, extract significantly downregulate the blood glucose, total cholesterol, triglycerides, low-density lipoprotein, and very low-density lipoprotein.

Withasomniferol C, a new potential SARS-CoV-2 main protease inhibitor from the Withania somnifera plant proposed by in silico approaches.

Exploring potent herbal medicine candidates is a promising strategy for combating a pandemic in the present global health crisis. In Ayurveda (a traditional medicine system in India), Withania somnifera (WS) is one of the most important herbs and it has been used for millennia as Rasayana (a type of juice) for its wide-ranging health benefits. WS phytocompounds display a broad spectrum of biological activities (such as antioxidant, anticancer and antimicrobial) modulate detoxifying enzymes, and enhance immunity. Inspired by the numerous biological actions of WS phytocompounds, the present investigation explored the potential of the WS phytocompounds against the SARS-CoV-2 main protease (3CLpro). We selected 11 specific withanolide compounds, such as withaphysalin, withasomniferol, and withafastuosin, through manual literature curation against 3CLpro. A molecular similarity analysis showed their similarity with compounds that have an established inhibitory activity against the SARS-CoV-2. In silico molecular docking and molecular dynamics simulations elucidated withasomniferol C (WS11) as a potential candidate against SARS-CoV-2 3CLpro. Additionally, the present work also presents a new method of validating docking poses using the AlteQ method.

Mapping a conservation research network to the Sustainable Development Goals

The United Nations Sustainable Development Goals (SDGs) provide a global blueprint to end extreme poverty, reduce inequality, and protect the planet. Progress toward these goals is falling short. Achieving the SDGs requires coordination among government, private industry, and nongovernmental organizations to align the actions of multiple sectors with SDG targets. Adapting an approach used by industry sectors, we mapped the Smithsonian Institution Working Land and Seascapes network to the SDGs. The network of programs aims to foster healthy and productive ecosystems through collaborations with diverse stakeholders. Across the network, we identified clear and measurable contributions to 16 of the 17 SDGs and specifically mapped past and current activities to 76 of the 169 targets, thereby demonstrating how conservation actions can contribute to achieving the SDGs, beyond SDGs 14 and 15. We also identified the need for clear results chain and greater capacity to achieve the SDGs and then provide examples of how different sectors can increase complementarity of their actions. By mapping activities to the SDGs, different sectors can increase alignment and strengthen collective contributions towards common global goals.

Quantum Chemical Studies on SARS-CoV-2-a Review

As soon as foreign substances like bacteria, fungi, chemicals and viruses (antigens) enter a human body, a protective protein (mostly Y-shaped), known as an antibody (immunoglobulin G - IgG) is produced by our immune system. But antibodies are not that much effective against viruses. Because viruses tend to mutate that leads to change in their shape which disturbs the necessitation of shape complementarity which limits the effectiveness of the antibody. Coronaviridae is a family of viruses that are responsible for SARS-CoV-2 (COVID-19) infection which is a contagious and serious viral infection. These spreads breathing of viral drops coming out of coughing and sneezing of infected persons. Touching of infected surface is also a prime cause of infection. Vaccines tend to train and prepare our body's immune system to recognize and fight off the infectious foreign bodies when they enter. After vaccination, if the antigens enter our body later, our immune system will be immediately ready to destroy them to prevent sickness. Lot of factors like vaccine inefficiency to different variants of existing viruses, age factor, denial of vaccination and previously existing illness make the issue still critical. To face this deadly, alarming global challenge and to prevent the future coronavirus outbreaks, various scientific communities have been toiling in multiple diverse studies about this newly emerged virus. In this review, we underline and summarize the recent research findings involving the SARS-CoV-2's structure, character, lifecycle, its target, finding out antivirus drugs (mainly S-protein of SARS-CoV-2 is targeted), inhibitors, a protocol to identify anti-COVID-19 candidates, detection of efficient and approved vaccines etc. © 2022 IEEE.

Sustainability in Small and Medium-Sized Enterprises: A Systematic Literature Review and Future Research Agenda

Main aim: This paper examines the main topics of research in the literature studying the topic of sustainability in small and medium-sized enterprises (SME), and aims at presenting a future research agenda. Method: We conducted a systematic literature review based on articles published between 2000 and 2020. From an initial set of 88 papers taken from WoS in the period under analysis, 42 papers were effectively analyzed. Main results: The results of an in-depth reading reveal four clusters representing the main topics of research in the field: sustainability and SMEs’ performance;green and environmental management issues;social and cultural issues and their impact on sustainability policies;values, skills, and capabilities. Key findings suggest that the following angles of research appear to be underexplored: theoretically grounded research;research using large samples;articles examining sustainability reporting;research looking into non-manufacturing sectors;work examining settings in developing countries;research undertaking international comparisons;articles exploring the complementarity between the literature on sustainability in SMEs and on family-owned businesses;and the influence of the social and cultural context on SMEs’ engagement with sustainability. Main contribution: This paper offers insights to academia, practitioners, and policy makers to help SMEs engaging with sustainability and may assist also the latter to develop strategies to improve SMEs’ social and environmental reporting. Given the current pandemic crisis, and the urgency for sustainable business practices, we expect to contribute to expanding knowledge in this field of research.

Shape Complementarity Optimization of Antibody-Antigen Interfaces: The Application to SARS-CoV-2 Spike Protein.

Many factors influence biomolecule binding, and its assessment constitutes an elusive challenge in computational structural biology. In this aspect, the evaluation of shape complementarity at molecular interfaces is one of the main factors to be considered. We focus on the particular case of antibody-antigen complexes to quantify the complementarities occurring at molecular interfaces. We relied on a method we recently developed, which employs the 2D Zernike descriptors, to characterize the investigated regions with an ordered set of numbers summarizing the local shape properties. Collecting a structural dataset of antibody-antigen complexes, we applied this method and we statistically distinguished, in terms of shape complementarity, pairs of the interacting regions from the non-interacting ones. Thus, we set up a novel computational strategy based on in silico mutagenesis of antibody-binding site residues. We developed a Monte Carlo procedure to increase the shape complementarity between the antibody paratope and a given epitope on a target protein surface. We applied our protocol against several molecular targets in SARS-CoV-2 spike protein, known to be indispensable for viral cell invasion. We, therefore, optimized the shape of template antibodies for the interaction with such regions. As the last step of our procedure, we performed an independent molecular docking validation of the results of our Monte Carlo simulations.

From emergency to structure: ways to fight Covid-19 via international cooperation in health from Brazil

This article argues the need for complementarity between emergency and structuring international cooperation in scenarios of health crises in developing countries. Through a review of contemporary literature and document analysis, it analyzes some aspects of the performance of global and Latin American institutions in the Covid-19 pandemic in light of this argument. It also makes a brief survey of forms of international cooperation that emerge from Brazil, with BRICS and Latin American partners, to fight the pandemic, which have a local and sectoral character: paradiplomacy, structuring networks and the role of local agents and health experts.

Hybridoma technology: is it still useful?

The isolation of single monoclonal antibodies (mAbs) against a given antigen was only possible with the introduction of the hybridoma technology, which is based on the fusion of specific B lymphocytes with myeloma cells. Since then, several mAbs were described for therapeutic, diagnostic, and research purposes. Despite being an old technique with low complexity, hybridoma-based strategies have limitations that include the low efficiency on B lymphocyte-myeloma cell fusion step, and the need to use experimental animals. In face of that, several methods have been developed to improve mAb generation, ranging from changes in hybridoma technique to the advent of completely new technologies, such as the antibody phage display and the single B cell antibody ones. In this review, we discuss the hybridoma technology along with emerging mAb isolation approaches, taking into account their advantages and limitations. Finally, we explore the usefulness of the hybridoma technology nowadays.