Background: The novel beta-coronavirus disease (COVID-19) has infected millions of people globally with high risk among male then female. However, the effect of COVID-19 andrology is still a subject of dispute. We planned to analyze the overall consequences of COVID-19 on semen parameters and male sex hormones. Main text: Systematic search was performed on MEDLINE and Scopus database until June 11 2021. We included observational studies, which reported mean ± standard deviation of the semen parameters and serum sex hormones of those reproductive-aged male recovered from COVID-19 and controls who did not suffered from COVID-19. We used Random-effect model to pool the studies, as heterogeneity was present. Heterogeneity was evaluated by Q test and I 2 . All studies were assessed with their quality and publication bias.We assessed 966 articles for eligibility and found 7 eligible studies meeting PICO criteria. This include 934 participants with mean age 37.34 ± 10.5. Random-effect model meta-analysis showed that men recovered form COVID-19 had semen parameters less than those who had not suffered from COVID-19. The overall mean difference (MD) [95% confidence interval (CI)] in semen volume, sperm concentration, sperm number, and progressive sperm motility was -0.20 (-0.45, 0.05), -16.59 (-34.82, 1.65), -45.44 (-84.56, -6.31), -1.73(-8.20, 4.75) respectively. Considering sex hormones; Luteinizing hormone and prolactin was found more among those recovered with the significant MD (95% CI) of 3.47 (1.59, 5.35) and 3.21 (1.71, 4.72) respectively. Conclusion: Both the semen parameters and sexual hormones were found to be affected after infected with COVID-19. However, the mechanism for testicular involvement remains doubtful.This systematic review and meta-analysis has been registered in PROSPERO (ID: CRD42021259445)

ABSTRACT ZIKV is a 11Kb positive stranded flavivirus transmitted by infected Aedes aegypti and by sexual intercourse. After a short period of viremia of 5-7 days, the virus is cleared, and infection resolved in 80% of individuals. However, around 27% of the fetuses from pregnant infected mothers may develop several fetal brain and ocular pathology. Here we show that murine and peripheral blood human neutrophils support ZIKV infection and replication both in vitro and in vivo , which may correlate to the facilitation of vertical transmission. ZIKV did not interfere with cell viability, neither induced ROS production nor the release of NETs by infected neutrophils. Also, ZIKV infection of neutrophils did not trigger a pro-inflammatory profile, as evidenced by qPCR and proteomic analysis. Interestingly, ZIKV-infected neutrophils were isolated from the placenta were highly infected. The transference of in vitro ZIKV-infected neutrophils to pregnant female mice favored the transference of viral particles to the fetus. Conversely, neutrophil depletion with monoclonal antibodies reduced fetal viral loads whereas the treatment with recombinant G-CSF has the opposite effect. In summary, although it has already been shown that circulating monocytes harbor ZIKV, to our knowledge, this is the first report demonstrating the role of neutrophils during ZIKV infection, and most important, that it may act as a trojan horse to placental tissue directly impacting the pathogenesis of congenital syndrome.

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light into mechanisms of action, safety and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCT) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. Reasons for CCP success and failure may be hidden in study details, which are usually difficult to explain to physicians and the public but provide fertile ground for designing next-generation studies. We analyzed variables associated with efficacy such as clinical settings, disease severity, CCP SARS-CoV-2 antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement or mortality), CCP provenance and time for collection, and criteria for efficacy. Focusing only on the results from the 30 available RCTs we noted that these were more likely to show signals of efficacy, including reductions in mortality, if the plasma neutralizing titer was ≥ 160 and the time to randomization was ≤ 9 days, consistent with passive antibody therapy efficacy requiring dosing with sufficient antibody. The fact that most studies revealed signals of efficacy despite variability in CCP and its use suggest likely therapeutic effects that become apparent despite the data noise. Despite the recent WHO guidelines discouraging CCP usage, the Omicron variant of concern is reminding us the superiority of polyclonal antibody therapies over monoclonal antibodies, and CCP from vaccinated convalescents is likely to be evaluated soon

Background: The invasive species Aedes albopictus , the Asian tiger mosquito, has undergone an extreme expansion by steady introductions as blind passengers in vehicles from the Mediterranean to South-West Germany. The more than 15 established populations in the State of Baden-Württemberg and Palatine (South-West Germany) have become a major nuisance and public health threat. Aedes albopictus deserves special attention as vector of arboviruses like dengue, chikungunya or Zika virus. In Germany, control of Ae. albopictus is implemented under the auspice of health departments and regulatory offices. Methods: The control strategy comprised three components or pillars: a) community participation (CP) based on the elimination or sanitation of breeding sites with the use of fizzy Bti-tablets (Culinex Tab plus); b) Door-to-Door (DtD) control by trained staff applying high doses of a Bti-water-dispersible granular formulation (Vectobac WG) aimed for a long-lasting killing effect; and c) the Sterile Insect Technique (SIT) to eliminate remaining Ae. albopictus populations. Prior to large scale routine city-wide treatments, the efficacy of the three elements was evaluated in laboratory and semi-field trials. Special emphasis was given to the mass release of Ae. albopictus sterile males. Results: More than 60% of the local residents joined the Community Participation within the large-scale control program. It was shown that the most effective element was the DtD intervention including the application of Vectobac WG (2700 ITU/mg after radiation with 25 kGy) to potential breeding sites (10 g/rainwater container, max. 200L ≙ 13,500ITU/L and 2.5g/container <50L) with a persistence of at least about three weeks. The average time required for the inspection and treatment per property was 27 minutes. In Ludwigshafen the larval source management resulted in a container index for Ae. albopictus below 1% in 2020 compared to 10.9% in 2019. The mean number of Aedes eggs/ovitrap were 4.3 in Ludwigshafen and 18.23 in Freiburg-Metzgergrün (SIT areas); while 22.4 in Freiburg-Gartenstadt (Control area). After the strong reduction of the Aedes population by Bti-application, the weekly release of 1,013 (Ludwigshafen) and 2,320 (Freiburg) sterile Ae. albopictus males/ha from May until October resulted in a high percentage of sterile eggs. In the trial area of Ludwigshafen the sterility of eggs reached 82.61% (mean: 60.52%; SD: 42.88%) and in Freiburg 62.68% (SD 28.21%). The natural sterility in the control area was 16.93±13.5%. The field results were in line with data obtained in cage tests under laboratory conditions where wild females mated with sterile males showed sterility rates of 87.53±9.15%. The sterility of eggs laid by females mated with unirradiated males was only 3.3±2.8%. The overall sterility of about 83% in Ludwigshafen indicates that our goal to almost eradicate the Ae. albopictus population could be achieved. Conclusions: It is shown that an integrated control program based on a strict monitoring scheme is most effective when it comprises three components, namely a) community participation, b) DtD intervention including long-lasting Bti-larviciding to strongly reduce Ae. albopictus populations and c) the release of sterile males to reduce the remaining Ae. albopictus population to a minimum or even to eradicate it. The combination of the use of Bti with SIT are most effective and selective tools against Ae. albopictus , one of the most dangerous mosquito vector species.

The recent global outbreaks of the ZIKA Virus (ZIKV) reported in 85 countries and territories caused severe complications such as microcephaly among neonates and Guillain-Barre Syndrome among the older population. Recently, an outbreak of ZIKV was reported from Thiruvananthapuram, the capital city of Kerala, India with 66 cases being reported so far. We conducted an outbreak investigation and the primary findings are described here. A cluster of ZIKV cases from the Kadakampalli / Anamugham administrative wards of the Thiruvananthapuram Municipal Corporation area was reported where Kerala Institute of Medical Sciences (KIMS) is located. Later many ZIKV cases were reported from other wards of the city. The density of known Aedes vectors was high in this region of the metropolitan city. Aedes albopictus , Aedes aegypti and Aedes vittatus collected from the focal area of the outbreak were found to be naturally infected with ZIKV. Male specimens of Ae. albopictus were naturally infected, indicating trans-ovarian transmission of the virus. This is first report of incrimination of Ae. albopictus and Ae. vittatus in ZIKV transmission from India. The virus was characterized and the partial sequences clustered with the Asian strain of ZIKV reported from India. The NS5 sequences of human and Ae. albopictus pools from Thiruvananthapuram were 100% similar indicating an ongoing active ZIKV transmission. The state health authorities were sensitized and appropriate containment and vector control measures have been initiated to contain the outbreak. This report underscores the importance of continued human and vector surveillance as well as genomic sequencing to understand the virus evolution and implications on public health.

COVID-19 represents the most severe global crisis to date whose public conversation can be studied in real time. To do so, we use a data set of over 350 million tweets and retweets posted by over 26 million English speaking Twitter users from January 13 to June 7, 2020. We characterize the retweet network to identify spontaneous clustering of users and the evolution of their interaction over time in relation to the pandemic's emergence. We identify several stable clusters (super-communities), and are able to link them to international groups mainly involved in science and health topics, national elites, and political actors. The science- and health-related super-community received disproportionate attention early on during the pandemic, and was leading the discussion at the time. However, as the pandemic unfolded, the attention shifted towards both national elites and political actors, paralleled by the introduction of country-specific containment measures and the growing politicization of the debate. Scientific super-community remained present in the discussion, but experienced less reach and became more isolated within the network. Overall, the emerging network communities are characterized by an increased self-amplification and polarization. This makes it generally harder for information from international health organizations or scientific authorities to directly reach a broad audience through Twitter for prolonged time. These results may have implications for information dissemination along the unfolding of long-term events like epidemic diseases on a world-wide scale.

SARS-CoV-2 (CoV2) is the viral agent responsible for the pandemic of the coronavirus disease 2019 (COVID-19). Vaccines are being deployed all over the world with good efficacy, but there is no approved antiviral treatment to date. This is particularly needed since the emergence of variants and the potential immune escape may prolong pandemic spreading of the infection for much longer than anticipated. Here, we developed a series of small molecules and identified RG10 as a potent antiviral compound against SARS-CoV-2 in cell lines and human airway epithelia (HAE). RG10 localizes to endoplasmic reticulum (ER) membranes, perturbing ER morphology and inducing ER stress. Yet, RG10 does not associate with SARS-CoV-2 replication sites although preventing virus replication. To further investigate the antiviral properties of our compound, we developed fluorescent SARS-CoV-2 viral particles allowing us to track virus arrival to ER membranes. Live cell imaging of replication-competent virus infection revealed that RG10 stalls the intracellular virus-ER dynamics. Finally, we synthesized RG10b, a stable version of RG10, that showed increased potency in vitro and in HAE with a pharmacokinetic half-life greater than 2 h. Together, our work reports on a novel fluorescent virus model and innovative antiviral strategy consisting of the perturbation of ER/virus dynamics, highlighting the promising antiviral properties of RG10 and RG10b.

ABSTRACT Non-specific protective effects of certain vaccines have been reported, and long-term boosting of innate immunity, termed trained immunity , has been proposed as one of the mechanisms mediating these effects. Several epidemiological studies suggested cross-protection between influenza vaccination and COVID-19. In a large academic Dutch hospital, we found that SARS-CoV-2 infection was less common among employees who had received a previous influenza vaccination: relative risk reductions of 37% and 49% were observed following influenza vaccination during the first and second COVID-19 waves, respectively. The quadrivalent inactivated influenza vaccine induced a trained immunity program that boosted innate immune responses against various viral stimuli and fine-tuned the anti-SARS-CoV-2 response, which may result in better protection against COVID-19. Influenza vaccination led to transcriptional reprogramming of monocytes and reduced systemic inflammation. These epidemiological and immunological data argue for potential benefits of influenza vaccination against COVID-19, and future randomized trials are warranted to test this possibility.

Emergency use authorization (EUA) is a power granted by Congress to FDA to expedite the availability and distribution of medical countermeasures during public health emergencies. This article reviews the history of FDA’s EUA authority from its inception in the post-9/11 era to its present-day use in response to COVID-19 in order to better understand and anticipate the limitations, potential, and risks of EUAs. We offer several reflections on the history of EUAs and ethical considerations relevant to their use in connection with COVID-19 (including a potential vaccine) and future emergencies. This history and analysis center around four main themes: (i) the effects that post-9/11 counterterrorist concerns have had on FDA’s ability to deal with naturally-occurring threats to public health and safety; (ii) political interference in efforts to defend the country against those threats; (iii) the question of where the risks posed by emergency countermeasures should fall, including with respect to legal liability for vaccine-related injuries; and (iv) the key ethical and policy issues confronting FDA in public health emergencies.

Mosquito-borne viruses including dengue, Zika and Chikungunya viruses as well as parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti (New Orleans strain) were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. Of the 400 compounds screened, we identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that significantly reduced Ae. aegypti larval motility compared to DMSO controls. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50s of 25.5 ± 5.0 μM and 22.3 ± 5.4 μM respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to Ae. aegypti adults at 100 μM and 10 μM and completely blocked egg laying when fed at 100 μM. Camptothecin and its derivatives, inhibitors of topoisomerase I, have known activity against several agricultural pests and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries. Both humans and mosquitoes express the highly conserved topoisomerase I target, however, the design of derivatives with differing pharmacokinetic properties may offer a promising route towards the development of insect-specificity of this chemistry.

Acute febrile illnesses are still a major cause of mortality and morbidity globally, particularly in low to middle income countries. The aim of this study was to determine any possible metabolic commonalities of patients infected with disparate pathogens that cause fever. Three liquid chromatography-mass spectrometry (LC-MS) datasets investigating the metabolic effects of malaria, leishmaniasis and Zika virus infection were used. The retention time (RT) drift between the datasets was determined using landmarks obtained from the standard reference mixtures generally used in the quality control of the LC-MS experiments. We used fitted Gaussian Process models (GPs) to perform a high level correction of the RT drift between the experiments, followed by standard peakset alignment between the samples with corrected RTs of the three LC-MS datasets. Statistical analysis, annotation and pathway analysis of the integrated peaksets were subsequently performed. Metabolic dysregulation patterns common across the datasets were identified, with kynurenine pathway being the most affected pathway between all three fever-associated datasets.

ABSTRACT Zika virus (ZIKV) is a positive-sense RNA flavivirus and can cause serious neurological disorders including microcephaly in infected fetus. As a mosquito-borne arbovirus, ZIKV enters bloodstream and is transmitted into the fetus through the placenta in pregnant women. Monocytes are considered one of the earliest blood cell types to be infected by ZIKV. As a first line defence, monocytes are crucial components in innate immunity and host responses and may impact viral pathogenesis in humans. Previous studies have shown that ZIKV infection can activate inflammasomes and induce proinflammatory cytokines in monocytes. In this report, we showed that ZIKV carried out a productive infection, which lead to cell death in human and murine monocytic cells. In addition to the presence of cleaved caspase-3, indicating that apoptosis was involved, we identified the cleaved caspase-1 and gasdemin D (GSDMD) as well as increased secretion of IL-1β and IL-18, suggesting that the inflammasome was activated that may lead to pyroptosis in infected monocytes. The pyroptosis was NLRP3-dependent and could be suppressed in the monocytes treated with shRNA to target and knockdown caspase-1, or an inhibited for caspase-1, indicating that the pyroptosis was triggered via a canonical approach. Our findings in this study demonstrate a concomitant occurrence of apoptosis and pyroptosis in ZIKV-infected monocytes, with multiple mechanisms involved in the cell death, which may have potentially significant impacts on viral pathogenesis in humans.

Partisan bias in fund portfolios is the effect of fund manager’s political affiliation on portfolio allocation decisions. I study two potential manifestations of this bias: biased expectations where managers become optimistic (pessimistic) when their party comes in (goes out of) the government, and in-group favoritism where managers choose higher holdings of politically aligned firms. I find strong evidence for the biased expectations channel, using recent data that includes the effects of the 2020 Presidential election. However, contrary to past literature, I find no evidence for in-group favoritism. I also document a partisan bias in holdings of stocks exposed to politicized topics (COVID-19 and Brexit). The COVID-19 result does not carry over to earlier pandemics (H1N1, Ebola and Zika).

ABSTRACT Dengue virus (DENV) NS1 is a multifunctional protein essential for viral replication. To gain insights into NS1 functions in mosquito cells, the protein interactome of DENV NS1 in C6/36 cells was investigated using a proximity biotinylation system and mass spectrometry. Approximately 14% of the 817 identified proteins coincide with interactomes obtained in vertebrate cells, including ontology groups of the oligosaccharide transferase complex, the chaperonin containing TCP-1, and nuclear import and export, vesicle localization and ribosomal proteins. Notably, other protein pathways such as epigenetic regulation and RNA silencing, not previously reported in vertebrate cells, were also found in the NS1 interactome in mosquito cells. Due to the novel interaction observed for NS1 and DIDO1 (Death Inducer-Obliterator 1), we further explored the role of DIDO1 in viral replication. Interactions between NS1 and DIDO1were corroborated in infected C6/36 and Aag2 cells, by colocalization and proximity ligation assays. Silencing DIDO1 expression in C6/36 and Aag2 cells results in a significant reduction in DENV and ZIKV replication and progeny production. Comparison of transcription analysis of mock or DENV infected C6/36 silenced for DIDO1, revealed variations in multiple gene expression pathways, including pathways associated with DENV infection such as RNA surveillance, IMD and Toll. These results suggest that DIDO1 is a host factor involved in the negative modulation of the antiviral response and necessary for flavivirus replication. Our findings uncover novel mechanisms of NS1 to promote DENV and ZIKV replication and add to the understanding of NS1 as a multifunctional protein. ABSTRACT IMPORTANCE Dengue is the most important mosquito-borne viral disease to humans. Dengue virus NS1 is a multifunctional protein essential for replication and modulation of innate immunity. To gain insights into NS1 functions, the protein interactome of dengue virus NS1 in Aedes albopictus cells was investigated using a proximity biotinylation system and mass spectrometry. Several protein pathways, not previously observed in vertebrate cells, such as epigenetic regulation and RNA silencing, were found as part of the NS1 interactome in mosquito cells. Among those, DIDO1 was found to be a necessary host factor for dengue and Zika virus replication in vertebrate and mosquito cells. Transcription analysis of infected mosquito cells silenced for DIDO1, revealed alterations of the IMD and Toll pathways, part of the antiviral response in mosquitoes. The results suggest that DIDO1 is a host factor involved in modulation of the antiviral response and necessary for flavivirus replication.

Introduction: As the COVID-19 pandemic spreads worldwide, reports about the neurological complications of SARS-CoV-2 are excessively increasing. However, there is still insufficient high-throughput data on neuronal cells infected with SARS-CoV-2 to help predict its neural pathogenesis. HCoV-OC43 is another member of the beta coronavirus family that has confirmed neuro-invasive effects and has available neural omics data. This study predicts the critical genes, biological processes, and pathways mediating in SARS-CoV-2 neurological manifestations using a systems biology approach. Method: We retrieved raw data related to SARS-CoV-2 and HCoV-OC43 infections from gene expression omnibus datasets (GSE147507 and GSE13879 respectively). We constructed gene regulatory networks for both infections, detected significant regulatory motifs by FANMOD software, and created their subnetworks. We also constructed PPI networks and identified the MCODE clusters. In the intersection of merged subnetworks of two viruses, the most critical genes were verified in GRN & PPI networks. We drug-repurposed for the selected target genes and performed the functional enrichment analysis using DAVID and String databases. Results: : Some of the top KEGG pathway results included NF-kappa B, Toll-like receptor, NOD-like receptor, MAPK, and Neurotrophin signaling pathways. The most essential identified genes included IL6, TNF, HOXA5, POU2F2, ITGB3, STAT1, YY1, E2F6, ESR1, FOXO3, FOXO1, MEF2A, ATF3, ATF4, DDIT3, TCF4, BCL2L2, and BMP4. These genes were also involved in mechanisms of other viral infections of the nervous system. This study repurposes nine medicines with effects on COVID-19 neurological complications. Some of the repurposed drugs were previously registered in clinical trials for COVID-19 treatment. Conclusion: We recommended some identified crucial genes and medications to investigate further their potential role in treating COVID-19 neurological complications.

Since the end of 2020, the mass vaccination has been actively promoted and seemed to be effective to bring the COVID-19 pandemic under control. However, the fact of immunity waning and the possible existence of antibody-dependent enhancement (ADE) make the situation uncertain. We developed a dynamic model of COVID-19 incorporating vaccination and immunity waning, which was calibrated by using the data of accumulative vaccine doses administered and the COVID-19 epidemic in 2020 in mainland China. We explored how long the current vaccination program can prevent China in a low risk of resurgence, and how ADE affects the long-term trajectory of COVID-19 epidemics. The prediction suggests that the vaccination coverage with at least one dose reach 95.87%, and with two-doses reach 77.92% on August 31, 2021. However, even with the mass vaccination, randomly introducing infected cases in the post-vaccination period can result in large outbreaks quickly in the presence of immunity waning, particularly for SARS-CoV-2 variants with higher transmission ability. The results showed that with the current vaccination program and a proportion of 50% population wearing masks, mainland China can be protected in a low risk of resurgence till 2023/01/18. However, ADE effect and higher transmission ability for variants would significantly shorten the protective period for more than 1 year. Furthermore, intermittent outbreaks can occur while the peak values of the subsequential outbreaks are decreasing, meaning that subsequential outbreaks boosted the immunity in the population level, which further indicating that catching-up vaccination program can help to mitigate the possible outbreaks, even avoid the outbreaks. The findings reveal that integrated effects of multiple factors, including immunity waning, ADE, relaxed interventions, and higher transmission ability of variants, make the control of COVID-19 much more difficult. We should get ready for a long struggle with COVID-19, and should not totally rely on COVID-19 vaccine.

Vertical transmission of Zika virus (ZIKV) leads with high frequency to congenital ZIKV syndrome (CZS), whose worst outcome is microcephaly. However, the mechanisms of congenital ZIKV neurodevelopmental pathologies, including direct cytotoxicity to neural progenitor cells (NPC), placental insufficiency, and immune responses, remain incompletely understood. At the cellular level, microcephaly typically results from death or insufficient proliferation of NPC or cortical neurons. NPCs replicate fast, requiring efficient DNA damage responses to ensure genome stability. Like congenital ZIKV infection, mutations in the polynucleotide 5’-kinase 3’-phosphatase (PNKP) gene, which encodes a critical DNA damage repair enzyme, results in recessive syndromes often characterized by congenital microcephaly with seizures (MCSZ). We thus tested whether there were any links between ZIKV and PNKP. Here we show that two PNKP phosphatase inhibitors or PNKP knockout inhibited ZIKV replication. PNKP relocalized from the nucleus to the cytoplasm in infected cells, co-localizing with the marker of ZIKV replication factories (RF) NS1 and resulting in functional nuclear PNKP depletion. Although infected NPC accumulated DNA damage, they failed to activate the DNA damage checkpoint kinases Chk1 and Chk2. ZIKV also induced activation of cytoplasmic CycA/CDK1 complexes, which trigger unscheduled mitotic entry. Inhibition of CDK1 activity inhibited ZIKV replication and the formation of RF, supporting a role of cytoplasmic CycA/CDK1 in RF morphogenesis. In brief, ZIKV infection induces mitotic catastrophe resulting from unscheduled mitotic entry in the presence of DNA damage. PNKP and CycA/CDK1 are thus host factors participating in ZIKV replication in NPC, and pathogenesis to neural progenitor cells. Significance The 2015-2017 Zika virus (ZIKV) outbreak in Brazil and subsequent international epidemic revealed the strong association between ZIKV infection and congenital malformations, mostly neurodevelopmental defects up to microcephaly. The scale and global expansion of the epidemic, the new ZIKV outbreaks (Kerala state, India, 2021), and the potential burden of future ones pose a serious ongoing risk. However, the cellular and molecular mechanisms resulting in microcephaly remain incompletely understood. Here we show that ZIKV infection of neuronal progenitor cells results in cytoplasmic sequestration of an essential DNA repair protein itself associated with microcephaly, with the consequent accumulation of DNA damage, together with an unscheduled activation of cytoplasmic CDK1/Cyclin A complexes in the presence of DNA damage. These alterations result in mitotic catastrophe of neuronal progenitors, which would lead to a depletion of cortical neurons during development.

ABSTRACT The causative agent of COVID-19 pandemic, the SARS-CoV-2 coronavirus, has a 29,903 bases positive-sense single-stranded RNA genome. RNAs exhibit about 100 modified bases that are essential for proper function. Among internal modified bases, the N 6 -methyladenosine, or m6A, is the most frequent, and is implicated in SARS-CoV-2 immune response evasion. Although the SARS-CoV-2 genome is RNA, almost all genomes sequenced so far are in fact, reverse transcribed complementary DNAs. This process reduces the true complexity of these viral genomes because incorporation of dNTPs hides RNA base modifications. Here, in this perspective paper, we present an initial exploration of the Nanopore direct RNA sequencing to assess the m6A residues in the SARS-CoV-2 sequences of ORF3a, E, M, ORF6, ORF7a, ORF7b, ORF8, N, ORF10 and the 3’-untranslated region. We identified 15 m6A methylated positions, of which, 6 are in ORF N. Also, because m6A is associated with the DRACH motif, we compared its distribution in major SARS-CoV-2 variants. Although DRACH is highly conserved among variants we show that variants Beta and Eta have a fourth position C>U change in DRACH at 28,884b that could affect methylation. The Nanopore technology offers a unique opportunity for the study of viral epitranscriptomics. This technique is PCR-free and is not sequencing-by-synthesis, therefore, no PCR bias and synthesis errors are introduced. The modified bases are preserved and assessed directly with no need for chemical treatments or antibodies. This is the first report of direct RNA sequencing of a Brazilian SARS-CoV-2 sample coupled with the identification of modified bases.

ABSTRACT The recent global Zika epidemics have revealed the significant threat that mosquito-borne viruses pose. There are currently no effective vaccines or prophylactics to prevent Zika virus (ZIKV) infection. Limiting exposure to infected mosquitoes is best way to reduce disease incidence. Recent studies have focused on targeting mosquito reproduction and immune responses to reduce transmission. In particular, previous work evaluated the effect of insulin signaling on antiviral JAK/STAT and RNAi in vector mosquitoes. In this work, we demonstrate that targeting insulin signaling through the repurposing of small molecule drugs results in the activation of both of these antiviral pathways. Activation of this coordinated response additively reduced ZIKV levels in Aedes aegypti mosquitoes. This effect included a quantitatively greater reduction in salivary gland ZIKV levels relative to single pathway activation, indicating the potential for field delivery of these small molecules to substantially reduce virus transmission.

This paper explores the impact of the Covid-19 crisis at the level of individual information behavior, based on an online survey among 308 participants from the German-speaking countries Austria, Germany and Switzerland in April and May 2020. The results show first that the Covid-19 crisis has led to an increased demand for reliable information. This goes alongside a significant increased use of public broadcasting, newspapers and information provided by public organizations. Second, the majority (84%) of the participants reported being satisfied with the information supply during the Covid-19 crisis. Participants who were less satisfied with the information supply used reliable sources significantly less frequently, specifically public television, national newspapers and information provided by public organizations. Third, the amount of Covid-19-related information led some participants to a feeling of information overload, which resulted in a reduction of information seeking and media use.

Background: Real-time surveillance of search behavior on the Internet has achieved accessibility in measuring disease activity. Here, we systematically assessed the associations between Internet search trends of GI symptoms and daily newly confirmed COVID-19 cases at the global and country levels. Methods: Relative search volumes (RSVs) of the terms of GI symptoms were derived from Internet search engines. Time-series analyses with autoregressive integrated moving average models were conducted to fit and forecast the RSVs trends of each GI symptom before and after the COVID-19 outbreak. Generalized additive models were used to quantify the effects of RSVs of GI symptoms on the incidence of COVID-19. In addition, dose-response analyses were applied to estimate the shape of the associations. Findings: The RSVs of GI symptoms could be characterized by seasonal variation and high correlation with symptoms of fever and cough at worldwide and country levels; especially, “diarrhea” and “loss of taste” were abnormally increased during the outbreak period of COVID-19 with elevated point changes of 1.31 and 8 times, respectively. In addition, these symptom terms could effectively predict the COVID-19 outbreak in advance underlying lag correlation at 12 and 5 days, respectively, and with mutual independence as well. The dose-response curves showed a consistent increase in daily COVID-19 risk with increasing search volumes of “diarrhea” and “loss of taste”. Interpretation: Our comprehensive research was the first and largest infodemiological study that revealed the advanced prediction of the COVID-19 outbreak via GI symptom indicators. Funding: None to declare. Declaration of Interest: We declare no competing interests.

Development of lab-on-a-chip (LOC) system based on integration of reverse transcription loop-mediated isothermal amplification (RT-LAMP) and microfluidic technology is expected to speed up SARS-CoV-2 diagnostics allowing early intervention. In the current work, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and RT-LAMP assays were performed on extracted RNA of 7 wastewater samples from COVID-19 hotspots. RT□LAMP assay was also performed on wastewater samples without RNA extraction. Current detection of SARS-CoV-2 is mainly by RT-qPCR of ORF (ORF1ab) and N genes so we targeted both to find the best surrogate marker for SARS-CoV-2 detection. We also performed RT-LAMP with/without RNA extraction inside microfluidic device to target both genes. Positivity rates of RT-qPCR and RT-LAMP performed on extracted RNA were 100.0% (7/7) and 85.7% (6/7), respectively. RT-qPCR results revealed that all 7 wastewater samples were positive for N gene (Ct range 37-39), and negative for ORF1ab, suggesting that N gene could be used as a surrogate marker for detection of SARS-CoV-2. RT-LAMP of N and ORF (ORF1a) genes performed on wastewater samples without RNA extraction indicated that all 7 samples remains pink (negative). The color remains pink in all microchannels except microchannels which subjected to RT-LAMP for targeting N region after RNA extraction (yellow color) in 6 out of 7 samples. This study shows that SARS-CoV-2 was successfully detected from wastewater samples using RT-LAMP in microfluidic chips.

ABSTRACT Background To counter the COVID-19 pandemic, mRNA vaccines, namely tozinameran and elasomeran, have been authorized in several countries. These next generation vaccines have shown high efficacy against COVID-19 and demonstrated a favorable safety profile. As widespread vaccinations efforts are taking place, incidents of myocarditis and pericarditis cases following vaccination have been reported. This safety signal has been recently confirmed by the European Medicine Agency and the U.S. Food and Drug Administration. This study aimed to investigate and analyze this safety signal using a dual pharmacovigilance database analysis. Methods This is as an observational study of reports of inflammatory heart reactions associated with mRNA COVID-19 vaccines reported in the World Health Organization’s global individual case safety report database (up to June 30 th 2021), and in the U.S. Vaccine Adverse Event Reporting System (VAERS, up to May 21 st 2021). Cases were described, and disproportionality analyses using reporting odds-ratios (ROR) and their 95% confidence interval (95%CI) were performed to assess relative risk of reporting according to patient sex and age. Results At a global scale, the inflammatory heart reactions most frequently reported were myocarditis (1241, 55%) and pericarditis (851, 37%), the majority requiring hospitalization (n=796 (64%)). Overall, patients were young (median age 33 [21-54] years). The main age group was 18-29 years old (704, 31%), and mostly males (1555, 68%). Pericarditis onset was delayed compared to myocarditis with a median time to onset of 8 [3-21] vs. 3 [2-6] days, respectively (p=0.001). Regarding myocarditis, an important disproportionate reporting in males (ROR, 9.4 [8.3-10.6]) as well as in adolescents (ROR, 22.3 [19.2-25.9]) and 18-29 years old (ROR, 6.6 [5.9-7.5]) compared to older patients were observed. Conclusions The inflammatory heart reactions, namely myocarditis and pericarditis, have been reported world-wide shortly following COVID-19 mRNA vaccination. An important disproportionate reporting among adolescents and young adults, particularly in males, was observed especially for myocarditis. Guidelines must take this specific risk into account and to optimize vaccination protocols according to sex and age. While the substantial benefits of COVID-19 vaccination still prevail over risks, clinicians and the public should be aware of these reactions and seek appropriate medical attention.

Dengue is the most prevalent arthropod-borne disease globally and affects approximately 2.5 billion people living in over 100 countries. The increasing geographic expansion of Aedes aegypti mosquitoes which transmit the virus has made dengue fever a global health concern. There are currently no approved antivirals available to treat dengue, and the only approved vaccine used in some countries is limited to seropositive patients. Treatment of dengue therefore remains largely supportive to date; hence research efforts are being intensified for the development of antivirals against dengue. The NS3 and NS5 nonstructural proteins have been the major targets for dengue antiviral development due to their indispensable enzymatic and biological functions in the viral replication process. NS5 is the largest and most conserved nonstructural protein encoded by flaviviruses including dengue. Its multifunctionality makes it an attractive target for antiviral development against dengue, but research efforts are hindered due to its limited structural characterization compared to the NS5 of other flaviviruses like the Zika virus. Increase in structural insights into the dengue NS5 protein will accelerate drug discovery efforts focused on NS5 as an antiviral target. In this review, we will give an overview of the current state of therapeutic development against dengue.

This paper investigates the impact of economic policy uncertainty (EPU) on the crash risk of US stock market during the COVID-19 pandemic. To this end, we use the GARCH-S (GARCH with skewness) model to estimate daily skewness as a proxy for the stock market crash risk. The empirical results show the significantly negative correlation between EPU and stock market crash risk, indicating the aggravation of EPU increase the crash risk. Moreover, the negative correlation gets stronger after the global COVID-19 outbreak, which shows the crash risk of the US stock market will be more affected by EPU during the pandemic.