Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

The objective of this work was to assess the overall survival, cause-specific survival and biochemical failure-free survival of a contemporary cohort of patients with localized prostate cancer (PCa) treated with intensity-modulated radiation therapy (IMRT) or radical prostatectomy (RP).

Objectives: To establish the role of BCG instillations in the incidence and mortality of COVID-19. Patients and methods: NMIBC patients in instillations with BCG (induction or maintenance) during 2019/2020 were included, establishing a COVID-19 group (with a diagnosis according to the national registry) and a control group (NO-COVID). The cumulative incidence (cases/total patients) and the case fatality rate (deaths/cases) were established, and compared with the national statistics for the same age group. T-test was used for continuous variables and Fisher's exact test for categorical variables. Results: 175 patients were included. Eleven patients presented CIS (11/175, 6.3%), 84/175 (48.0%) Ta and 68/175 (38.9%) T1. Average number of instillations = 13.25 ± 7.4. One hundred sixty-seven patients (95.4%) had complete induction. Forty-three patients (cumulative incidence 24.6%) were diagnosed with COVID-19. There is no difference between COVID-19 and NO-COVID group in age, gender or proportion of maintenance completed. COVID-19 group fatality rate = 1/43 (2.3%). Accumulated Chilean incidence 70–79 years = 6.3%. Chilean fatality rate 70–79 years = 14%. Conclusions: According to our results, patients with NMIBC submitted to instillations with BCG have a lower case-fatality rate than the national registry of patients between 70 and 79 years (2.3% vs. 14%, respectively). Intravesical BCG could decrease the mortality due to COVID-19, so instillation schemes should not be suspended in a pandemic.

In its prefusion state, the SARS-CoV-2 spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating its functions. After the binding process of its S1 subunit (S1) with ACE2, the spike protein (S) undergoes a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed—using large-scale molecular dynamics simulations—that the application of external electric fields (EFs) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild-type spike protein, as well of the Alpha, Beta, and Gamma variants, leaving a structure which cannot be recognized anymore by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of the RBD of the prefusion state of S to moderate EF (as weak as 10⁴ V/m), but, more importantly, we also show that, in contrast, the S2 subunit of the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the connection between the prefusion-state metastability of the SARS-CoV-2 spike protein and its susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 10⁸ V/m) like most globular proteins.

Common models of circadian rhythms are typically constructed as compartmental reactions of well-mixed biochemicals, incorporating a negative-feedback loop consisting of several intermediate reaction steps essentially required to produce oscillations. Spatial transport of each reactant is often represented as an extra compartmental reaction step. Contrary to this traditional understanding, in this Letter we demonstrate that a single activation-repression biochemical reaction pair is sufficient to generate sustained oscillations if the sites of both reactions are spatially separated and molecular transport is mediated by diffusion. Our proposed scenario represents the simplest configuration in terms of the participating chemical reactions and offers a conceptual basis for understanding biological oscillations and inspiring in vitro assays aimed at constructing minimal clocks.