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[This corrects the article DOI: 10.1371/journal.pcbi.1010527.].

The relationship between macroscale electrophysiological recordings and the dynamics of underlying neural activity remains unclear. We have previously shown that low frequency EEG activity (

COVID-19 vaccines have been widely used to reduce the incidence and disease severity of COVID-19. Questions have lately been raised about the possibility of an association between COVID-19 vaccines and myocarditis, an inflammatory condition affecting the myocardium, or the middle layer of the heart. Myocarditis can be caused by infections, immune reactions, or toxic exposure. The incidence rate of myocarditis and pericarditis was calculated to be 5.98 instances per million COVID-19 vaccine doses delivered, which is less than half of the incidences after SARS-CoV-2 infection. Myocarditis rates in people aged 12 to 39 years are around 12.6 cases per million doses following the second dose of mRNA vaccination. Adolescent men are more likely than women to develop myocarditis after receiving mRNA vaccines. The objectives of this systematic review and meta-analysis are to find out how often myocarditis occurs after receiving the COVID-19 vaccine, as well as the risk factors and clinical repercussions of this condition. Nevertheless, the causal relationship between vaccination and myocarditis has been difficult to establish, and further research is required. It is also essential to distinguish between suggested cases of myocarditis and those confirmed by endomyocardial biopsy.

Alphaviruses have been engineered as expression vectors for different strategies of cancer therapy including immunotherapy and cancer vaccine development. Administration of recombinant virus particles, RNA replicons and plasmid DNA-based replicons provide great flexibility for alphavirus applications. Immunization and delivery studies have demonstrated therapeutic efficacy in the form of reduced tumor growth, tumor regression and eradication of established tumors in different animal models for cancers such as brain, breast, colon, cervical, lung, ovarian, pancreas, prostate cancers, and melanoma. Furthermore, vaccinated animals have showed protection against challenges with tumor cells. A limited number of clinical trials in the area of brain, breast, cervical, colon prostate cancers and melanoma vaccines has been conducted. Particularly, immunization of cervical cancer patients elicited immune responses and therapeutic activity in all patients included in a phase I clinical trial. Moreover, stable disease and partial responses were observed in breast cancer patients and prolonged survival was achieved in colon cancer patients.

Open reading frame 8 (ORF8) shows one of the highest levels of variability among accessory proteins in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits the presentation of viral antigens by the major histocompatibility complex class I (MHC-I), which interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 in evading immunity and plays a role in SARS-CoV-2 replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein, defines the B.1.1.7 lineage of SARS-CoV-2, engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) with the Q27STOP mutations were identified among 49,055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents, which include Africa, Asia, Europe and South America. Based on various quantitative features, such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, nine possible T-ORF8 unique variants were defined. The question as to whether T-ORF8 variants function similarly to the wild type ORF8 is yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.

Self-replicating RNA viruses have become attractive delivery vehicles for therapeutic applications. They are easy to handle, can be rapidly produced in large quantities, and can be delivered as recombinant viral particles, naked or nanoparticle-encapsulated RNA, or plasmid DNA-based vectors. The self-replication of RNA in infected host cells provides the means for generating much higher transgene expression levels and the possibility to apply substantially reduced amounts of RNA to achieve similar expression levels or immune responses compared to conventional synthetic mRNA. Alphaviruses and flaviviruses, possessing a single-stranded RNA genome of positive polarity, as well as measles viruses and rhabdoviruses with a negative-stranded RNA genome, have frequently been utilized for therapeutic applications. Both naturally and engineered oncolytic self-replicating RNA viruses providing specific replication in tumor cells have been evaluated for cancer therapy. Therapeutic efficacy has been demonstrated in animal models. Furthermore, the safe application of oncolytic viruses has been confirmed in clinical trials. Multiple myeloma patients treated with an oncolytic measles virus (MV-NIS) resulted in increased T-cell responses against the measles virus and several tumor-associated antigen responses and complete remission in one patient. Furthermore, MV-CEA administration to patients with ovarian cancer resulted in a stable disease and more than doubled the median overall survival.

Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons. Alphavirus vectors have been utilized for the expression of various antigens targeting different types of cancers, and cytotoxic and antitumor genes. The most common alphavirus vectors are based on the Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, but the oncolytic M1 alphavirus has also been used. Delivery of immunostimulatory cytokine genes has been the basis for immunotherapy demonstrating efficacy in different animal tumor models for brain, breast, cervical, colon, lung, ovarian, pancreatic, prostate and skin cancers. Typically, therapeutic effects including tumor regression, tumor eradication and complete cure as well as protection against tumor challenges have been observed. Alphavirus vectors have also been subjected to clinical evaluations. For example, therapeutic responses in all cervical cancer patients treated with an alphavirus vector expressing the human papilloma virus E6 and E7 envelope proteins have been achieved.

It is well established that pre-existing comorbid conditions such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), cancers, and chronic obstructive pulmonary disease (COPD) are associated with increased severity and fatality of COVID-19. The increased death from COVID-19 is due to the unavailability of a gold standard therapeutic and, more importantly, the lack of understanding of how the comorbid conditions and COVID-19 interact at the molecular level, so that personalized management strategies can be adopted. Here, using multi-omics data sets and bioinformatics strategy, we identified the pathway crosstalk between COVID-19 and diabetes, hypertension, CVDs, CKDs, and cancers. Further, shared pathways and hub gene-based targets for COVID-19 and its associated specific and combination of comorbid conditions are also predicted towards developing personalized management strategies. The approved drugs for most of these identified targets are also provided towards drug repurposing. Literature supports the involvement of our identified shared pathways in pathogenesis of COVID-19 and development of the specific comorbid condition of interest. Similarly, shared pathways- and hub gene-based targets are also found to have potential implementations in managing COVID-19 patients. However, the identified targets and drugs need further careful evaluation for their repurposing towards personalized treatment of COVID-19 cases having pre-existing specific comorbid conditions we have considered in this analysis. The method applied here may also be helpful in identifying common pathway components and targets in other disease-disease interactions too.

Single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses and rhabdoviruses are characterized by their capacity of highly efficient self-amplification of RNA in host cells, which make them attractive vehicles for vaccine development. Particularly, alphaviruses and flaviviruses can be administered as recombinant particles, layered DNA/RNA plasmid vectors carrying the RNA replicon and even RNA replicon molecules. Self-amplifying RNA viral vectors have been used for high level expression of viral and tumor antigens, which in immunization studies have elicited strong cellular and humoral immune responses in animal models. Vaccination has provided protection against challenges with lethal doses of viral pathogens and tumor cells. Moreover, clinical trials have demonstrated safe application of RNA viral vectors and even promising results in rhabdovirus-based phase III trials on an Ebola virus vaccine. Preclinical and clinical applications of self-amplifying RNA viral vectors have proven efficient for vaccine development and due to the presence of RNA replicons, amplification of RNA in host cells will generate superior immune responses with significantly reduced amounts of RNA delivered. The need for novel and efficient vaccines has become even more evident due to the global COVID-19 pandemic, which has further highlighted the urgency in challenging emerging diseases.

The current coronavirus COVID-19 pandemic, which originated in Wuhan, China, has raised significant social, psychological and economic concerns in addition to direct medical issues. The rapid spread of severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 to almost every country on the globe and the failure to contain the infections have contributed to fear and panic worldwide. The lack of available and efficient antiviral drugs or vaccines has further worsened the situation. For these reasons, it cannot be overstated that an accelerated effort for the development of novel drugs and vaccines is needed. In this context, novel approaches in both gene therapy and vaccine development are essential. Previous experience from SARS- and MERS-coronavirus vaccine and drug development projects have targeted glycoprotein epitopes, monoclonal antibodies, angiotensin receptor blockers and gene silencing technologies, which may be useful for COVID-19 too. Moreover, existing antivirals used for other types of viral infections have been considered as urgent action is necessary. This review aims at providing a background of coronavirus genetics and biology, examples of therapeutic and vaccine strategies taken and potential innovative novel approaches in progress.

Gene therapy applications of oncolytic viruses represent an attractive alternative for cancer treatment. A broad range of oncolytic viruses, including adenoviruses, adeno-associated viruses, alphaviruses, herpes simplex viruses, retroviruses, lentiviruses, rhabdoviruses, reoviruses, measles virus, Newcastle disease virus, picornaviruses and poxviruses, have been used in diverse preclinical and clinical studies for the treatment of various diseases, including colon, head-and-neck, prostate and breast cancer as well as squamous cell carcinoma and glioma. The majority of studies have focused on immunotherapy and several drugs based on viral vectors have been approved. However, gene therapy for malignant melanoma based on viral vectors has not been utilized to its full potential yet. This review represents a summary of the achievements of preclinical and clinical studies using viral vectors, with the focus on malignant melanoma.

In many cases, the computation of a neural system can be reduced to a receptive field, or a set of linear filters, and a thresholding function, or gain curve, which determines the firing probability; this is known as a linear/nonlinear model. In some forms of sensory adaptation, these linear filters and gain curve adjust very rapidly to changes in the variance of a randomly varying driving input. An apparently similar but previously unrelated issue is the observation of gain control by background noise in cortical neurons: the slope of the firing rate versus current (f-I) curve changes with the variance of background random input. Here, we show a direct correspondence between these two observations by relating variance-dependent changes in the gain of f-I curves to characteristics of the changing empirical linear/nonlinear model obtained by sampling. In the case that the underlying system is fixed, we derive relationships relating the change of the gain with respect to both mean and variance with the receptive fields derived from reverse correlation on a white noise stimulus. Using two conductance-based model neurons that display distinct gain modulation properties through a simple change in parameters, we show that coding properties of both these models quantitatively satisfy the predicted relationships. Our results describe how both variance-dependent gain modulation and adaptive neural computation result from intrinsic nonlinearity.