The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity.

Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site.

Field-scale evaluation of struvite phosphorus and nitrogen leaching relative to monoammonium phosphate.

Struvite (MgNH PO ·6H O) is a wastewater-derived phosphorus (P) fertilizer with potential to reduce P as well as nitrogen (N) losses due to its low water solubility. To test hypothesized lower P and N losses from struvite relative to monoammonium phosphate (MAP), field experiments with a randomized-complete block design were conducted in central (Urbana) Illinois on an Endoaquoll-Argiudoll complex and in southern (Ewing) Illinois on a Fragiudalf-Hapludalf complex. Fertilizer was broadcast applied in the fall prior to spring planting of soybean (Glycine max L.

Inhibition of Human Coronaviruses by Combinations of Host-Targeted and Direct-Acting Antivirals.

Antiviral compounds targeting cellular metabolism are part of the therapeutic arsenal to control the spread of virus infection, either as sole treatment or in combination with direct-acting antivirals (DAA) or vaccines. Here, we describe the effect of two of them, lauryl gallate (LG) and valproic acid (VPA) both exhibiting a wide antiviral spectrum, against infection by coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-2. A consistent 2 to 4-log-decrease in virus yields was observed in the presence of each antiviral, with an average IC value of 1.

Deregulation of ζ-carotene desaturase in Arabidopsis and tomato exposes a unique carotenoid-derived redundant regulation of floral meristem identity and function.

A level of redundancy and interplay among the transcriptional regulators of floral development safeguards a plant's reproductive success and ensures crop production. In the present study, an additional layer of complexity in the regulation of floral meristem (FM) identity and flower development is elucidated linking carotenoid biosynthesis and metabolism to the regulation of determinate flowering. The accumulation and subsequent cleavage of a diverse array of ζ-carotenes in the chloroplast biogenesis 5 (clb5) mutant of Arabidopsis results in the reprogramming of meristematic gene regulatory networks establishing FM identity mirroring that of the FM identity master regulator, APETALA1 (AP1).

Plastids: diving into their diversity, their functions, and their role in plant development.

Plastids are a group of essential, heterogenous semi-autonomous organelles characteristic of plants that perform photosynthesis and a diversity of metabolic pathways that impact growth and development. Plastids are remarkably dynamic and can interconvert in response to specific developmental and environmental cues, functioning as a central metabolic hub in plant cells. By far the best studied plastid is the chloroplast, but in recent years the combination of modern techniques and genetic analyses has expanded our current understanding of plastid morphological and functional diversity in both model and non-model plants.

The role of carotenoids as a source of retrograde signals: impact on plant development and stress responses.

Communication from plastids to the nucleus via retrograde signal cascades is essential to modulate nuclear gene expression, impacting plant development and environmental responses. Recently, a new class of plastid retrograde signals has emerged, consisting of acyclic and cyclic carotenoids and/or their degradation products, apocarotenoids. Although the biochemical identity of many of the apocarotenoid signals is still under current investigation, the examples described herein demonstrate the central roles that these carotenoid-derived signals play in ensuring plant development and survival.

The 6-Minute Walk Test predicts long-term physical improvement among intensive care unit survivors: a prospective cohort study.

Objective: To evaluate the ability of the 6-Minute Walk Test to predict long-term physical functional status improvement among intensive care unit survivors.

Methods: Thirty-two intensive care unit survivors were prospectively evaluated from February 2017 to August 2018 in a post-intensive care unit outpatient clinic in Brazil. Individuals with intensive care unit stays > 72 hours (emergency admissions) or > 120 hours (elective admissions) attending the post-intensive care unit clinic four months after intensive care unit discharge were consecutively enrolled.

Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination.

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and its numerous spike mutations, which have the potential to evade neutralizing antibodies elicited by COVID-19 vaccines. Here we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants who had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that a heterologous CoronaVac prime vaccination of two doses followed by a BNT162b2 booster induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and the Delta variant, resembling the titers obtained after two doses of mRNA vaccines.

Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability.

Foot-and-mouth disease virus (FMDV) is a picornavirus that exhibits an extremely acid sensitive capsid. This acid lability is directly related to its mechanism of uncoating triggered by acidification inside cellular endosomes. Using a collection of FMDV mutants we have systematically analyzed the relationship between acid stability and the requirement for acidic endosomes using ammonium chloride (NHCl), an inhibitor of endosome acidification.

Whole-Genome Sequences of SARS-CoV-2 Isolates from the Dominican Republic.

Here, we report the genome sequences of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains that were obtained from symptomatic individuals with travel histories during community surveillance in the Dominican Republic in 2020. These sequences provide a starting point for further genomic studies of gene flow and molecular diversity in the Caribbean nation. Phylogenetic analysis suggests that all genomes correspond to the B.

Immunogenicity of Foot-and-Mouth Disease Virus Dendrimer Peptides: Need for a T-Cell Epitope and Ability to Elicit Heterotypic Responses.

An approach based on a dendrimer display of B- and T-cell epitopes relevant for antibody induction has been shown to be effective as a foot-and-mouth disease (FMD) vaccine. BT dendrimers combining two copies of the major FMD virus (FMDV) type O B-cell epitope (capsid proteinVP1 (140-158)) covalently linked to a heterotypic T-cell epitope from non-structural protein 3A (21-35), henceforth BT-3A, has previously been shown to elicit high neutralizing antibody (nAb) titers and IFN-γ-producing cells in both mice and pigs. Here, we provide evidence that the B- and T-cell epitopes need to be tethered to a single molecular platform for successful T-cell help, leading to efficient nAb induction in mice.

Reassessing the evolution of the 1-deoxy-D-xylulose 5-phosphate synthase family suggests a possible novel function for the DXS class 3 proteins.

The methylerythritol 4-phosphate (MEP) pathway is of paramount importance for generating plastidial isoprenoids. The first enzyme of the MEP pathway, 1-deoxy-D-xylulose-5-phosphate synthase (DXS), catalyzes a flux-controlling step. In plants the DXS gene family is composed of three distinct classes with non-redundant functions.

Peptide-Based Vaccines: Foot-and-Mouth Disease Virus, a Paradigm in Animal Health.

Vaccines are considered one of the greatest global health achievements, improving the welfare of society by saving lives and substantially reducing the burden of infectious diseases. However, few vaccines are fully effective, for reasons ranging from intrinsic limitations to more contingent shortcomings related, e.g.

Randomized clinical trial to compare the efficacy of ivermectin versus placebo to negativize nasopharyngeal PCR in patients with early COVID-19 in Peru (SAINT-Peru): a structured summary of a study protocol for randomized controlled trial.

Objectives: The primary objective is to determine the effect of a daily dose of ivermectin administered in three consecutive days to non-severe COVID-19 patients with no more than 96 hours of symptoms, on the detection of SARS-CoV-2 RNA by PCR from nasopharyngeal swabs at day seven post-treatment initiation. The secondary objectives are: 1. To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the nasopharyngeal swab on days 4, 7, 14 and 21 post-treatment initiation 2.

Swine T-Cells and Specific Antibodies Evoked by Peptide Dendrimers Displaying Different FMDV T-Cell Epitopes.

Dendrimeric peptide constructs based on a lysine core that comprises both B- and T-cell epitopes of foot-and-mouth disease virus (FMDV) have proven a successful strategy for the development of FMD vaccines. Specifically, BT dendrimers displaying two copies of the major type O FMDV antigenic B-cell epitope located on the virus capsid [VP1 (140-158)], covalently linked to a heterotypic T-cell epitope from either non-structural protein 3A [3A (21-35)] or 3D [3D (56-70)], named BT-3A and BT-3D, respectively, elicit high levels of neutralizing antibodies (nAbs) and IFN-γ-producing cells in pigs. To assess whether the inclusion and orientation of T-3A and T-3D T-cell epitopes in a single molecule could modulate immunogenicity, dendrimers with T epitopes juxtaposed in both possible orientations, i.

Deconvoluting apocarotenoid-mediated retrograde signaling networks regulating plastid translation and leaf development.

Signals originating within plastids modulate organelle differentiation by transcriptionally regulating nuclear-encoded genes. These retrograde signals are also integral regulators of plant development, including leaf morphology. The clb5 mutant displays severe leaf morphology defects due to Apocarotenoid Signal 1 (ACS1) accumulation in the developmentally arrested plastid.

Association of Porcine Swine Leukocyte Antigen (SLA) Haplotypes with B- and T-Cell Immune Response to Foot-and-Mouth Disease Virus (FMDV) Peptides.

Dendrimer peptides are promising vaccine candidates against the foot-and-mouth disease virus (FMDV). Several B-cell epitope (BT) dendrimers, harboring a major FMDV antigenic B-cell site in VP1 protein, are covalently linked to heterotypic T-cell epitopes from 3A and/or 3D proteins, and elicited consistent levels of neutralizing antibodies and IFN-γ-producing cells in pigs. To address the contribution of the highly polymorphic nature of the porcine MHC (SLA, swine leukocyte antigen) on the immunogenicity of BT dendrimers, low-resolution (Lr) haplotyping was performed.

Immunogenicity of a Dendrimer BT Peptide Harboring a T-Cell Epitope From FMDV Non-structural Protein 3D.

Synthetic dendrimer peptides are a promising strategy to develop new FMD vaccines. A dendrimer peptide, termed BT-3A, which harbors two copies of the major FMDV antigenic B-cell site [VP1 (140-158)], covalently linked to a heterotypic T-cell from the non-structural protein 3A [3A (21-35)], has been shown to protect pigs against viral challenge. Interestingly, the modular design of this dendrimer peptide allows modifications aimed at improving its immunogenicity, such as the replacement of the T-cell epitope moiety.

Designing Functionally Versatile, Highly Immunogenic Peptide-Based Multiepitopic Vaccines against Foot-and-Mouth Disease Virus.

A broadly protective and biosafe vaccine against foot-and-mouth disease virus (FMDV) remains an unmet need in the animal health sector. We have previously reported solid protection against serotype O FMDV afforded by dendrimeric peptide structures harboring virus-specific B- and T-cell epitopes, and also shown such type of multivalent presentations to be advantageous over simple B-T-epitope linear juxtaposition. Chemically, our vaccine platforms are modular constructions readily made from specified B- and T-cell epitope precursor peptides that are conjugated in solution.

A bivalent B-cell epitope dendrimer peptide can confer long-lasting immunity in swine against foot-and-mouth disease.

Foot-and-mouth disease virus (FMDV) causes a widely extended contagious disease of livestock. We have previously reported that a synthetic dendrimeric peptide, termed B T(mal), consisting of two copies of a B-cell epitope [VP1(140-158)] linked through maleimide groups to a T-cell epitope [3A(21-35)] of FMDV, elicits potent B- and T-cell-specific responses and confers solid protection in pigs to type O FMDV challenge. Longer duration of the protective response and the possibility of inducing protection after a single dose are important requirements for an efficient FMD vaccine.

A Single Dose of Dendrimer BT Peptide Vaccine Partially Protects Pigs against Foot-and-Mouth Disease Virus Infection.

Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals whose control relies on efficient vaccination. We have reported that dendrimer peptide BT, with two copies of FMDV B-cell epitope VP1 (136-154) linked through maleimide units to T-cell epitope 3A (21-35)], elicits potent B- and T-cell specific responses and confers solid protection in pigs to type-O FMDV challenge after two doses of peptide. Herein we now show that BT evokes specific protective immune responses after administration of a single dose of either 2 or 0.

Uncovering the functional residues of isoprenoid biosynthesis enzyme HDS.

The methylerythritol phosphate (MEP) pathway is responsible for producing isoprenoids, metabolites with essential functions in the bacterial kingdom and plastid-bearing organisms including plants and Apicomplexa. Additionally, the MEP-pathway intermediate methylerythritol cyclodiphosphate (MEcPP) serves as a plastid-to-nucleus retrograde signal. A suppressor screen of the high MEcPP accumulating mutant plant () led to the isolation of 3 revertants (designated -) resulting from independent intragenic substitutions of conserved amino acids in the penultimate MEP-pathway enzyme, hydroxymethylbutenyl diphosphate synthase (HDS).

Inhibition of Porcine Viruses by Different Cell-Targeted Antiviral Drugs.

Antiviral compounds targeting cellular metabolism instead of virus components have become an interesting issue for preventing and controlling the spread of virus infection, either as sole treatment or as a complement of vaccination. Some of these compounds are involved in the control of lipid metabolism and/or membrane rearrangements. Here, we describe the effect of three of these cell-targeting antivirals: lauryl gallate (LG), valproic acid (VPA), and cerulenin (CRL) in the multiplication of viruses causing important porcine diseases.