Enhancing the Prefusion Conformational Stability of SARS-CoV-2 Spike Protein Through Structure-Guided Design

The worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented and the impact on public health and the global economy continues to be devastating. Although early therapies such as prophylactic antibodies and vaccines show great promise, there are concerns about the long-term efficacy and universal applicability of these therapies as the virus continues to mutate. Thus, protein-based immunogens that can quickly respond to viral changes remain of continued interest. The Spike protein, the main immunogen of this virus, displays a highly dynamic trimeric structure that presents a challenge for therapeutic development. Here, guided by the structure of the Spike trimer, we rationally design new Spike constructs that show a uniquely high stability profile while simultaneously remaining locked into the immunogen-desirable prefusion state. Furthermore, our approach emphasizes the relationship between the highly conserved S2 region and structurally dynamic Receptor Binding Domains (RBD) to enable vaccine development as well as the generation of antibodies able to resist viral mutation.

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COVID-19 dominant D614G mutation in the SARS-CoV-2 spike protein desensitizes its temperature-dependent denaturation

10.1101/2021.03.28.437426 ◽

2021 ◽

Author(s):

Tzu-Jing Yang ◽

Pei-Yu Yu ◽

Yuan-Chih Chang ◽

Chu-Wei Kuo ◽

Kay-Hooi Khoo ◽

...

Keyword(s):

Receptor Binding ◽

Vaccine Development ◽

Spike Protein ◽

Temperature Dependent ◽

Dominant Form ◽

Binding Domains ◽

Cryo Electron Microscopy ◽

The Impact ◽

Multiple Receptor ◽

Shed Light

AbstractThe D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, making it the dominant form in the COVID-19 pandemic. Here we demonstrated by cryo-electron microscopy that the D614G mutation does not significantly perturb the structure of the spike protein, but multiple receptor binding domains are in an upward conformation poised for host receptor binding. The impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics, and to significantly increase the thermal stability under physiological pH. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation, and suggest an approach for better design of spike-protein based conjugates for vaccine development.

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Plasmodium falciparum schizont stage transcriptome variation among clinical isolates and laboratory-adapted clones

10.1101/329532 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sarah J Tarr ◽

Ofelia Díaz-Ingelmo ◽

Lindsay B Stewart ◽

Suzanne E Hocking ◽

Lee Murray ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Vaccine Development ◽

Ex Vivo ◽

Experimental Studies ◽

Differentially Expressed ◽

Clinical Isolates ◽

Schizont Stage ◽

Variable Expression ◽

The Impact

AbstractMalaria parasite genes exhibit variation in both sequence and expression level. There is much information on sequence polymorphism, but less resolution on natural variation in transcriptomes of parasites at specific developmental stages. This is largely because it is challenging to obtain highly replicated sampling of transcriptomes to overcome potentially confounding technical and biological variation. We address the issue in the major human parasite Plasmodium falciparum by obtaining RNA-seq profiles of multiple independent replicate preparations of mature schizont-stage parasites from a panel of clinical isolates recently established in culture and from long-term laboratory-adapted clones. With a goal of robustly identifying variably expressed genes, we show that increasing the numbers of biological sample replicates greatly improves the discovery rate. Generally, six independent replicates of each parasite culture is recommendable as being significantly to lower numbers, although for highly expressed genes variable expression can be detected when fewer replicates are available. A broad comparison identifies genes differing in relative expression between cultured clinical isolates and laboratory-adapted clones. Genes more highly expressed in the laboratory-adapted clones include an AP2 transcription factor gene Pf3D7_0420300 and putative methyl transferase genes. The variable expression of several known merozoite invasion ligands is confirmed, and previously uncharacterised genes are shown to be differentially expressed among clinical isolates. New RT-qPCR assays validate the variation in transcript levels of these genes, and allow quantitation of expression to be extended to a wider panel of clinical isolate samples. These variably expressed genes are new candidates for investigation as potential determinants of alternative parasite developmental pathways or targets of immunity.Author summaryUnderstanding parasite diversity and adaptation may require characterisation of gene expression variation, and is vital if chemotherapeutic or vaccine development is to consider new candidate targets, but it is technically challenging to generate precise data on clinical isolates. Here, we analyse the transcriptomes of mature Plasmodium falciparum schizonts using RNA-sequencing, using large numbers of biological replicate samples to minimise the impact of inter-replicate variation on observed patterns of differential expression. This identifies genes that are differentially expressed in long term laboratory-adapted parasites and recently cultured clinical isolates, as well as among different clinical isolates. In additional samples of schizonts grown in the first cycle ex vivo prior to any erythrocyte invasion, expression levels of a selected panel of these genes vary among isolates, but mean levels are similar to those in the continuously cultured clinical isolates, indicating that the latter are useful for experimental studies requiring biological replication.

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An International Commentary on Dysphagia and Dysphonia During the COVID-19 Pandemic

Dysphagia ◽

10.1007/s00455-021-10396-z ◽

2022 ◽

Author(s):

Anna Miles ◽

Jackie McRae ◽

Gemma Clunie ◽

Patricia Gillivan-Murphy ◽

Yoko Inamoto ◽

...

Keyword(s):

Healthcare Workers ◽

Vaccine Development ◽

Clinical Symptoms ◽

Well Being ◽

Primary Data ◽

International Expert ◽

Travel Restrictions ◽

The Impact ◽

Health And Well Being

AbstractCOVID-19 has had an impact globally with millions infected, high mortality, significant economic ramifications, travel restrictions, national lockdowns, overloaded healthcare systems, effects on healthcare workers’ health and well-being, and large amounts of funding diverted into rapid vaccine development and implementation. Patients with COVID-19, especially those who become severely ill, have frequently developed dysphagia and dysphonia. Health professionals working in the field have needed to learn about this new disease while managing these patients with enhanced personal protective equipment. Emerging research suggests differences in the clinical symptoms and journey to recovery for patients with COVID-19 in comparison to other intensive care populations. New insights from outpatient clinics also suggest distinct presentations of dysphagia and dysphonia in people after COVID-19 who were not hospitalized or severely ill. This international expert panel provides commentary on the impact of the pandemic on speech pathologists and our current understanding of dysphagia and dysphonia in patients with COVID-19, from acute illness to long-term recovery. This narrative review provides a unique, comprehensive critical appraisal of published peer-reviewed primary data as well as emerging previously unpublished, original primary data from across the globe, including clinical symptoms, trajectory, and prognosis. We conclude with our international expert opinion on what we have learnt and where we need to go next as this pandemic continues across the globe.

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TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Viruses ◽

10.3390/v13030384 ◽

2021 ◽

Vol 13 (3) ◽

pp. 384

Author(s):

Mai Kishimoto ◽

Kentaro Uemura ◽

Takao Sanaki ◽

Akihiko Sato ◽

William W. Hall ◽

...

Keyword(s):

Viral Entry ◽

Vaccine Development ◽

Spike Protein ◽

Tissue Tropism ◽

Type Ii ◽

Angiotensin Converting Enzyme 2 ◽

Exogenous Expression ◽

Transmembrane Serine Protease ◽

The Impact

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.

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The Long-Term Performance Consequences Of Strategic Partnerships In High Tech Industries

Journal of Applied Business Research (JABR) ◽

10.19030/jabr.v29i1.7569 ◽

2012 ◽

Vol 29 (1) ◽

pp. 217 ◽

Cited By ~ 2

Author(s):

Carolyn M. Callahan ◽

Rod E. Smith ◽

Angela Wheeler Spencer

Keyword(s):

Global Economy ◽

Operating Performance ◽

Customer Relationships ◽

High Tech ◽

Strategic Partnerships ◽

Product Cycles ◽

Long Term Impact ◽

Term Performance ◽

The Impact

In this paper, we examine how inter-firm partnerships impact long-term operating performance. With a global economy, rapid product cycles, capital constraints and advances in technology, firms seldom possess all the capabilities necessary to maintain and grow market share. Consequently, firms rely on a variety of partnerships. Theory suggests that firms enter such relationships to improve performance through access to new products, new markets, or new capabilities. Yet, relatively little is known about the long-term impact of collaborative arrangements such as alliances and established major customer relationships, although such dual partnership arrangements can have a major impact on the firms performance success. Our empirical results indicate that inter-firm partnerships affect operating performance, but the impact often depends on the industry, the nature of the firm, and the type of partnership.

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Spatiotemporal dissemination pattern of SARS-CoV-2 B1.1.28-derived lineages introduced into Uruguay across its southeastern border with Brazil.

10.1101/2021.07.05.21259760 ◽

2021 ◽

Author(s):

Natalia Rego ◽

Tamara Fernandez-Calero ◽

Ighor Arantes ◽

Veronica Noya ◽

daiana mir ◽

...

Keyword(s):

Spike Protein ◽

Partial Replacement ◽

Viral Dynamics ◽

Rio Grande Do Sul ◽

Viral Genomes ◽

Replacement Process ◽

Functional Relevance ◽

The Impact ◽

Epidemic Wave

During the first nine months of the SARS-CoV-2 pandemic, Uruguay successfully kept it under control, even when our previous studies support a recurrent viral flux across the Uruguayan-Brazilian border that sourced several local outbreaks in Uruguay. However, towards the end of 2020, a remarkable exponential growth was observed and the TETRIS strategy was lost. Here, we aimed to understand the factors that fueled SARS-CoV-2 viral dynamics during the first epidemic wave in the country. We recovered 84 whole viral genomes from patients diagnosed between November, 2020 and February, 2021 in Rocha, a sentinel eastern Uruguayan department bordering Brazil. The lineage B.1.1.28 was the most prevalent in Rocha during November-December 2020, P.2 became the dominant one during January-February 2021, while the first P.1 sequences corresponds to February, 2021. The lineage replacement process agrees with that observed in several Brazilian states, including Rio Grande do Sul (RS). We observed a one to three month delay between the appearance of P.2 and P.1 in RS and their subsequent detection in Rocha. The phylogenetic analysis detected two B.1.1.28 and one P.2 main Uruguayan SARS-CoV-2 clades, introduced from the southern and southeastern Brazilian regions into Rocha between early November and mid December, 2020. One synonymous mutation distinguishes the sequences of the main B.1.1.28 clade in Rocha from those widely distributed in RS. The minor B.1.1.28 cluster, distinguished by several mutations, harbours non-synonymous changes in the Spike protein: Q675H and Q677H, so far not concurrently reported. The convergent appearance of S:Q677H in different viral lineages and its proximity to the S1/S2 cleavage site raise concerns about its functional relevance. The observed S:E484K-VOI P.2 partial replacement of previously circulating lineages in Rocha might have increased transmissibility as suggested by the significant decrease in Ct values. Our study emphasizes the impact of Brazilian SARS-CoV-2 epidemics in Uruguay and the need of reinforcing real-time genomic surveillance on specific Uruguayan border locations, as one of the key elements for achieving long-term COVID-19 epidemic control.

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COVID-19, Oil Price, Bitcoin, and US Economic Policy Uncertainty: Evidence from ARDL Model

International Journal of Economics and Finance ◽

10.5539/ijef.v13n11p88 ◽

2021 ◽

Vol 13 (11) ◽

pp. 88

Author(s):

Hanan Naser

Keyword(s):

Economic Policy ◽

Financial Market ◽

Global Economy ◽

Positive Impact ◽

Oil Price ◽

Market Volatility ◽

Policy Uncertainty ◽

Economic Policy Uncertainty ◽

The Impact

The pandemic of coronavirus (COVID-19) creates fear and uncertainty causing extraordinary disruption to financial markets and global economy. Witnessing the fastest selloff in the American stock market in history with a plunge of more than 28% in S&P 500 has increased the volatility of global financial market to exceed the level observed during the financial crisis of 2008. On the other hand, Bitcoin value has shown considerable stability in the last couple of months peaking at $10,367.53 in the mid of February 2020. In this context, the aim of this paper is to investigate the impact of COVID-19 numbers on Bitcoin price taking into consideration number of controlling variables including WTI-oil price, S&P 500 index, financial market volatility, gold prices, and economic policy uncertainty of the US. To do so, ARDL estimation has been applied using daily data from December 31, 2019 till May 20, 2020. Key findings reveal that the daily reported cases of new infections have a marginal positive impact on Bitcoin price in the long term. However, the indirect impact associated with the fear of COVID-19 pandemic via financial market stress cannot be neglected. Bitcoin can also serve as a hedging tool against the economic policy uncertainty in the long term. In the short run, while the returns of economic policy uncertainty have no impact on Bitcoin price, the growth in the new cases of COVID-19 infection and returns of financial market volatility have more positive significant impact on Bitcoin returns.

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The effect of a pandemic on the Life Sciences industry

EJPPS EUROPEAN JOURNAL OF PARENTERAL AND PHARMACEUTICAL SCIENCES ◽

10.37521/ejpps25204 ◽

2020 ◽

Author(s):

Cliodhna McDonough ◽

Emily Lockey

Keyword(s):

Vaccine Development ◽

Negative Impact ◽

Healthcare Facility ◽

Preventative Care ◽

Short Term ◽

Global Pandemic ◽

The Us ◽

The Impact ◽

Life Sciences Industry

Pharmaceutical, healthcare and biotech companies have been at the forefront of the COVID-19 response, from drug trials and vaccine development to the production of personal protective equipment (PPE) and ventilators. The industry has a unique ability and responsibility to help the world respond to the global pandemic, both by working collaboratively to deliver solutions to the virus and also by maintaining the supply of medically important products to those who need them. As in all industries, business in the sector has been disrupted by the virus. This is largely driven by a reduction in healthcare provider and patient interactions as hospitals redirect resources toward COVID-19, and patients avoid healthcare facility visits and postpone preventative care. The impact on specific companies will depend on the diversity of their portfolio and their largest revenue areas. For example, roughly two thirds of Merck’s global Human Health revenue is comprised of physician-administered products and decreased volumes during the pandemic are expected to have a negative impact on revenues. Whilst much of the pandemic impact will be short term, peaking over the next quarter in conjunction with the peak of the virus in the US and Europe and settling towards the end of the year, it is likely we will see some long term structural change in the industry as global attitudes towards health shift in the wake of the pandemic.

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Problems of the development of the banking sector after the pandemy

SHS Web of Conferences ◽

10.1051/shsconf/202111001038 ◽

2021 ◽

Vol 110 ◽

pp. 01038

Author(s):

Fedor Buraev ◽

Marina Danilina ◽

Elena Kostromina ◽

Anna Silaeva

Keyword(s):

Global Economy ◽

Banking Sector ◽

Banking System ◽

Subsequent Development ◽

The Real ◽

Long Term Consequences ◽

The Impact

The coronavirus pandemic has negatively impacted the global economy. The banking sector is no exception. The authors analyze the impact of the coronavirus on the functioning and subsequent development of the banking sector in Russia. If we consider this pandemic as a one-time event, then the banking system will recover quickly enough, and there will be no tragic long-term consequences. However, if we talk about the coronavirus pandemic as a recurring event that will occur at intervals of two or even three times a year, then the real consequences are still difficult to assess.

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Are We Ready for An Economic Meltdown? The Impact of COVID19 on Sri Lanka Economy

10.31124/advance.12230765.v1 ◽

2020 ◽

Author(s):

Prageeth Weerathunga ◽

WHMS Samarathunga

Keyword(s):

Sri Lanka ◽

Central Bank ◽

Global Economy ◽

Annual Reports ◽

Research Articles ◽

Sri Lankan ◽

Long Term Effects ◽

Policy Measures ◽

The Impact

This essay briefly discusses the impact of COVID-19 on the global economy and the Sri Lankan Economy. The essay begins with an analysis of the global scenario and then discusses the impact on the Sri Lankan Economy. Information required for analysis was obtained from a variety of sources, such as newspapers, websites, blogs, annual reports from the central bank, research articles, books, etc. In this article, we identified different industry that are likely to be seriously affected by the COVID-19 pandemic. The impact on these industries has been discussed and, where applicable, quantified effects have been identified. Finally, a number of policy measures have been proposed to minimize long-term effects on the economy.

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