Squalene in oil-based adjuvant improves the immunogenicity of SARS-CoV-2 RBD and confirms safety in animal models.

COVID-19 pandemic has accelerated the development of vaccines against its etiologic agent, SARS-CoV-2. However, the emergence of new variants of the virus lead to the generation of new alternatives to improve the current sub-unit vaccines in development. In the present report, the immunogenicity of the Spike RBD of SARS-CoV-2 formulated with an oil-in-water emulsion and a water-in-oil emulsion with squalene was evaluated in mice and hamsters. The RBD protein was expressed in insect cells and purified by chromatography until >95% purity. The protein was shown to have the appropriate folding as determined by ELISA and flow cytometry binding assays to its receptor, as well as by its detection by hamster immune anti-S1 sera under non-reducing conditions. In immunization assays, although the cellular immune response elicited by both adjuvants were similar, the formulation based in water-in-oil emulsion and squalene generated an earlier humoral response as determined by ELISA. Similarly, this formulation was able to stimulate neutralizing antibodies in hamsters. The vaccine candidate was shown to be safe, as demonstrated by the histopathological analysis in lungs, liver and kidney. These results have shown the potential of this formulation vaccine to be evaluated in a challenge against SARS-CoV-2 and determine its ability to confer protection.

Intranasal vaccination of hamsters with a Newcastle disease virus vector expressing the S1 subunit protects animals against SARS-CoV-2 disease.

The coronavirus disease-19 (COVID-19) pandemic has already claimed millions of lives and remains one of the major catastrophes in the recorded history. While mitigation and control strategies provide short term solutions, vaccines play critical roles in long term control of the disease. Recent emergence of potentially vaccine-resistant and novel variants necessitated testing and deployment of novel technologies that are safe, effective, stable, easy to administer, and inexpensive to produce. Here we developed three recombinant Newcastle disease virus (rNDV) vectored vaccines and assessed their immunogenicity, safety, and protective efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice and hamsters. Intranasal administration of rNDV-based vaccine candidates elicited high levels of neutralizing antibodies. Importantly, the nasally administrated vaccine prevented lung damage, and significantly reduced viral load in the respiratory tract of vaccinated animal which was compounded by profound humoral immune responses. Taken together, the presented NDV-based vaccine candidates fully protected animals against SARS-CoV-2 challenge and warrants evaluation in a Phase I human clinical trial as a promising tool in the fight against COVID-19.

A Recombinant Turkey Herpesvirus Expressing the F Protein of Newcastle Disease Virus Genotype XII Generated by NHEJ-CRISPR/Cas9 and Cre-LoxP Systems Confers Protection against Genotype XII Challenge in Chickens.

In this study, we developed a new recombinant virus rHVT-F using a Turkey herpesvirus (HVT) vector, expressing the fusion (F) protein of the genotype XII Newcastle disease virus (NDV) circulating in Peru. We evaluated the viral shedding and efficacy against the NDV genotype XII challenge in specific pathogen-free (SPF) chickens. The F protein expression cassette was inserted in the unique long (UL) UL45-UL46 intergenic locus of the HVT genome by utilizing a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 gene-editing technology via a non-homologous end joining (NHEJ) repair pathway. The rHVT-F virus, which expressed the F protein stably in vitro and in vivo, showed similar growth kinetics to the wild-type HVT (wtHVT) virus. The F protein expression of the rHVT-F virus was detected by an indirect immunofluorescence assay (IFA), Western blotting, and a flow cytometry assay. The presence of an NDV-specific IgY antibody was detected in serum samples by an enzyme-linked immunosorbent assay (ELISA) in SPF chickens vaccinated with the rHVT-F virus. In the challenge experiment, the rHVT-F vaccine fully protects a high, and significantly reduced, virus shedding in oral at 5 days post-challenge (dpc). In conclusion, this new rHVT-F vaccine candidate is capable of fully protecting SPF chickens against the genotype XII challenge.

Oral ivermectin for the treatment of red scrotum syndrome.

Red scrotum syndrome is an infrequently reported dermatosis characterized by scrotal erythema accompanied by burning, pain, or dysesthesia. It has been increasingly associated with prolonged use of topical corticosteroids. Treatment is challenging and symptoms may persist for months or years after discontinuation of the topical corticosteroids. We report three cases successfully treated with oral ivermectin.

Total synthesis and mechanism of action of the antibiotic armeniaspirol A.

Emerging antimicrobial resistance urges the discovery of antibiotics with unexplored, resistance-breaking mechanisms. Armeniaspirols represent a novel class of antibiotics with a unique spiro[4.4]non-8-ene scaffold and potent activities against Gram-positive pathogens. We report a concise total synthesis of (±) armeniaspirol A in six steps with a yield of 20.3% that includes the formation of the spirocycle through a copper-catalyzed radical cross-coupling reaction. In mechanistic biological experiments, armeniaspirol A exerted potent membrane depolarization, accounting for the pH-dependent antibiotic activity. Armeniaspirol A also disrupted the membrane potential and decreased oxygen consumption in mitochondria. In planar lipid bilayers and in unilamellar vesicles, armeniaspirol A transported protons across membranes in a protein-independent manner, demonstrating that armeniaspirol A acted as a protonophore. We provide evidence that this mechanism might account for the antibiotic activity of multiple chloropyrrole-containing natural products isolated from various origins that share a 4-acylphenol moiety coupled to chloropyrrole as a joint pharmacophore. We additionally describe an efflux-mediated mechanism of resistance against armeniaspirols.

Publisher Correction: Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A case of lichen aureus successfully treated with 595 nm wavelength pulsed-dye laser.

BACKGROUND: Lichen aureus (LA) is a variant of pigmented purpuric dermatosis (PPDs) that typically presents with the acute onset of a solitary, unilateral, purple to rust-yellow colored lichenoid patch or plaque on lower extremities. Treatment remains challenging and is based on anecdotal case reports often with poor results. AIMS: Describe a case of LA successfully treated with 595 nm wavelength pulsed-dye laser (PDL). PATIENT/METHOD: A 46-year-old woman with segmental LA was treated using a 595 nm PDL at a uniform spot size of 10 mm, with pulse durations of 10 milliseconds and fluence of 6 J/cm2. The patient had received previous treatments with no improvement. RESULTS: Clearance was archived after three sessions with PDL. Sessions were performed at intervals of 4 weeks, with no serious adverse events nor recurrence. CONCLUSION: We hypothesize the favorable clinical outcome with PDL is due to the affinity of the wavelength for oxyhemoglobin (allowing uniform vessel penetration and energy delivery to fragile capillaries and intraluminal blood) and to its anti-inflammatory profile. PDL seems to be an alternative for patients with progressive LA that have failed other therapies.

Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish.

Two essential key events in acrylamide (ACR) acute neurotoxicity are the formation of adducts with nucleophilic sulfhydryl groups on cysteine residues of selected proteins in the synaptic terminals and the depletion of the glutathione (GSx) stores in neural tissue. The use of N-acetylcysteine (NAC) has been recently proposed as a potential antidote against ACR neurotoxicity, as this chemical is not only a well-known precursor of the reduced form of glutathione (GSH), but also is an scavenger of soft electrophiles such as ACR. In this study, the suitability of 0.3 and 0.75 mM NAC to protect against the neurotoxic effect of 0.75 mM ACR has been tested in vivo in adult zebrafish. NAC provided only a mild to negligible protection against the changes induced by ACR in the motor function, behavior, transcriptome and proteome. The permeability of NAC to cross blood-brain barrier (BBB) was assessed, as well as the ACR-scavenging activity and the gamma-glutamyl-cysteine ligase (γ-GCL) and acylase I activities. The results show that ACR not only depletes GSx levels but also inhibits it synthesis from NAC/cysteine, having a dramatic effect over the glutathione system. Moreover, results indicate a very low NAC uptake to the brain, probably by a combination of low BBB permeability and high deacylation of NAC during the intestinal absorption. These results strongly suggest that the use of NAC is not indicated in ACR acute neurotoxicity treatment.

Further characterization of the zebrafish model of acrylamide acute neurotoxicity: gait abnormalities and oxidative stress.

Occupational, accidental, or suicidal exposure to acrylamide (ACR) may result in a neurotoxic syndrome. Development of animal models of acrylamide neurotoxicity is necessary for increasing our mechanistic understanding of this syndrome and developing more effective therapies. A new model for acute ACR neurotoxicity has been recently developed in adult zebrafish. Whereas the results of the initial characterization were really promising, a further characterization is needed for testing the construct validity of the model. In this study, the presence of gait abnormalities has been investigated by using ZebraGait, software specifically designed to analyze the kinematics of fish swimming in a water tunnel. The results of the kinematic analyses demonstrated that the model exhibits mild-to-moderate gait abnormalities. Moreover, the model exhibited negative scototaxis, a result confirming a phenotype of anxiety comorbid with depression phenotype. Interestingly, depletion of the reduced glutathione levels was found in the brain without a concomitant increase in oxidative stress. Finally, hypolocomotion and positive geotaxis exhibited by this model were fully recovered 5 days after transferring the fish to clean fish-water. All this data support the validity of the ACR acute neurotoxicity model developed in adult zebrafish.

Prevalence of skin diseases among hospitals in the public healthcare system of a developing country.

BACKGROUND: Skin diseases in the population are universal, common, and can cause significant economic burden. The impact of skin diseases in the national public healthcare system is complex and poorly studied. This study analyzes the prevalence of skin diseases in a hospital setting within the National Public Health System of Mexico and describes the main associated characteristics. METHODS: Information was obtained from the 2015 hospital discharge database of the public healthcare system of Mexico. Pathologies that result in a direct dermatological condition were included according to chapter XII of the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD - 10) and grouped according to the classification of the report, The burden of skin diseases in the United States. RESULTS: In 2015, a total of 9,230,968 hospital discharges were registered nationwide, of which 170,917 discharges (1.85%) reported a dermatological disease as the main diagnosis; five states account for 40.79% of the cases reported in Mexico. Half of all the cases corresponded to skin infections (32.08%, n = 54,843) and non-cancerous skin growths (27.80%, n = 47,515), and 59.71% were adult patients between 18 and 65 years of age. CONCLUSIONS: Understanding of the configuration of skin diseases in a hospital setting and public healthcare system is warranted to develop effective public policies and research for the development of effective, safe, high-quality care processes for the main groups of identified diseases.

Prevalencia mundial de la diabetes mellitus tipo 2 y su relación con el índice de desarrollo humano

Objetivo. Evaluar la relación entre la prevalencia de diabetes mellitus tipo 2 (DM2) y el índice de desarrollo humano (IDH) por región del mundo en el período 2010–2015. Método. Se utilizaron los datos de la Federación Internacional de Diabetes para la prevalencia de DM2 (2010–2015) y el IDH del Programa de las Naciones Unidas para el Desarrollo. Se analizaron correlaciones lineales de Spearman entre el IDH y la prevalencia de DM2 y se hicieron regresiones lineales para estimar la relación entre ambos. Resultados. Se observó que a menor IDH menores son las prevalencias de DM2, y a mayor IDH, mayores son las prevalencias de DM2. A nivel mundial, el IDH explica 8,6% de la varianza de la prevalencia de DM2 (P < 0,0001) y que este comportamiento fue diferente en cada región del mundo. Conclusiones. El IDH puede influir en la prevalencia de DM2, aunque la relación depende de cada país, región y año analizado.

Objective. To evaluate the relationship between the prevalence of type 2 diabetes mellitus (DM2) and the Human Development Index (HDI), by region of the world in the period 2010-2015. Method. International Diabetes Federation data were used for DM2 prevalence (2010-2015), together with HDI data (United Nations Development Program). Spearman linear correlations between HDI data and DM2 prevalence were analyzed, and linear regressions were done to estimate the relationship between the two. Results. It was observed that lower HDI scores corresponded to lower DM2 prevalence rates, and higher HDI scores to higher DM2 prevalence. At the global level, the HDI explains the 8.6% variance of DM2 prevalence (P < 0.0001) and shows that the situation was different in each region of the world. Conclusions. While HDI score may be associated with DM2 prevalence, the relationship between them differs from region to region and from country to country, and depends on the particular year analyzed.

Objetivo. Avaliar a relação entre a prevalência de diabetes mellitus tipo 2 (DM2) e o índice de desenvolvimento humano (IDH) por região do mundo no período de 2010 a 2015. Métodos. Foram utilizados dados da Federação Internacional de Diabetes para a prevalência da DM2 (2010–2015) e o IDH do Programa das Nações Unidas para o Desenvolvimento. Foram analisadas as correlações lineares de Spearman entre o IDH e a prevalência de DM2 e feitas regressões lineares para estimar a relação entre ambos. Resultados. Observou-se que quanto mais baixo o IDH, menores são as prevalências de DM2, e quanto mais alto o IDH, maiores são prevalências de DM2. Ao nível mundial, o IDH explica 8,6% da variança da prevalência de DM2 (P < 0,0001) e este comportamento difere em cada região do mundo. Conclusões. O IDH pode influir na prevalência de DM2, embora a relação dependa de cada país, região e ano analisados.

Synthesis and Structural Revision of the Fungal Tetramic Acid Metabolite Spiroscytalin.

Spiroscytalin, a natural 3-spirotetramic acid of hitherto uncertain absolute configuration, was synthesized for the first time by a one-pot Knoevenagel-IMDA reaction of an l-phenylalanine-derived tetramic acid and (R)-2-methyl-deca-6E,8E-dienal. Its absolute configuration was assigned by the known configurations of the starting compounds and by NOESY correlations. Its identity with the natural isolate was proved by the comparison of the NMR and circular dichroism spectra and of the specific optical rotations. Its absolute configuration (3R,5S,6S,7R,11S,14R) is enantiomeric to that originally proposed by the isolating group. This natural isomer of spiroscytalin showed moderate activity against Candida albicans and good activity against an export-deficient mutant of Escherichia coli.

[Global prevalence of type 2 diabetes mellitus and its relationship with the Human Development IndexPrevalência mundial da diabetes mellitus tipo 2 e sua relação com o índice de desenvolvimento humano]. / Prevalencia mundial de la diabetes mellitus tipo 2 y su relación con el índice de desarrollo humano.

OBJECTIVE: To evaluate the relationship between the prevalence of type 2 diabetes mellitus (DM2) and the Human Development Index (HDI), by region of the world in the period 2010-2015. METHOD: International Diabetes Federation data were used for DM2 prevalence (2010-2015), together with HDI data (United Nations Development Program). Spearman linear correlations between HDI data and DM2 prevalence were analyzed, and linear regressions were done to estimate the relationship between the two. RESULTS: It was observed that lower HDI scores corresponded to lower DM2 prevalence rates, and higher HDI scores to higher DM2 prevalence. At the global level, the HDI explains the 8.6% variance of DM2 prevalence (P < 0.0001) and shows that the situation was different in each region of the world. CONCLUSIONS: While HDI score may be associated with DM2 prevalence, the relationship between them differs from region to region and from country to country, and depends on the particular year analyzed.

OBJETIVO: Avaliar a relação entre a prevalência de diabetes mellitus tipo 2 (DM2) e o índice de desenvolvimento humano (IDH) por região do mundo no período de 2010 a 2015. MÉTODOS: Foram utilizados dados da Federação Internacional de Diabetes para a prevalência da DM2 (2010­2015) e o IDH do Programa das Nações Unidas para o Desenvolvimento. Foram analisadas as correlações lineares de Spearman entre o IDH e a prevalência de DM2 e feitas regressões lineares para estimar a relação entre ambos. RESULTADOS: Observou-se que quanto mais baixo o IDH, menores são as prevalências de DM2, e quanto mais alto o IDH, maiores são prevalências de DM2. Ao nível mundial, o IDH explica 8,6% da variança da prevalência de DM2 (P < 0,0001) e este comportamento difere em cada região do mundo. CONCLUSÕES: O IDH pode influir na prevalência de DM2, embora a relação dependa de cada país, região e ano analisados.

Prevalencia mundial de la diabetes mellitus tipo 2 y su relación con el índice de desarrollo humano / Global prevalence of type 2 diabetes mellitus and its relationship with the Human Development Index / Prevalência mundial da diabetes mellitus tipo 2 e sua relação com o índice de desenvolvimento humano

RESUMEN Objetivo Evaluar la relación entre la prevalencia de diabetes mellitus tipo 2 (DM2) y el índice de desarrollo humano (IDH) por región del mundo en el período 2010-2015. Método Se utilizaron los datos de la Federación Internacional de Diabetes para la prevalencia de DM2 (2010-2015) y el IDH del Programa de las Naciones Unidas para el Desarrollo. Se analizaron correlaciones lineales de Spearman entre el IDH y la prevalencia de DM2 y se hicieron regresiones lineales para estimar la relación entre ambos. Resultados Se observó que a menor IDH menores son las prevalencias de DM2, y a mayor IDH, mayores son las prevalencias de DM2. A nivel mundial, el IDH explica 8,6% de la varianza de la prevalencia de DM2 (P < 0,0001) y que este comportamiento fue diferente en cada región del mundo. Conclusiones El IDH puede influir en la prevalencia de DM2, aunque la relación depende de cada país, región y año analizado.

ABSTRACT Objective To evaluate the relationship between the prevalence of type 2 diabetes mellitus (DM2) and the Human Development Index (HDI), by region of the world in the period 2010-2015. Method International Diabetes Federation data were used for DM2 prevalence (2010-2015), together with HDI data (United Nations Development Program). Spearman linear correlations between HDI data and DM2 prevalence were analyzed, and linear regressions were done to estimate the relationship between the two. Results It was observed that lower HDI scores corresponded to lower DM2 prevalence rates, and higher HDI scores to higher DM2 prevalence. At the global level, the HDI explains the 8.6% variance of DM2 prevalence (P < 0.0001) and shows that the situation was different in each region of the world. Conclusions While HDI score may be associated with DM2 prevalence, the relationship between them differs from region to region and from country to country, and depends on the particular year analyzed.

RESUMO Objetivo Avaliar a relação entre a prevalência de diabetes mellitus tipo 2 (DM2) e o índice de desenvolvimento humano (IDH) por região do mundo no período de 2010 a 2015. Métodos Foram utilizados dados da Federação Internacional de Diabetes para a prevalência da DM2 (2010-2015) e o IDH do Programa das Nações Unidas para o Desenvolvimento. Foram analisadas as correlações lineares de Spearman entre o IDH e a prevalência de DM2 e feitas regressões lineares para estimar a relação entre ambos. Resultados Observou-se que quanto mais baixo o IDH, menores são as prevalências de DM2, e quanto mais alto o IDH, maiores são prevalências de DM2. Ao nível mundial, o IDH explica 8,6% da variança da prevalência de DM2 (P < 0,0001) e este comportamento difere em cada região do mundo. Conclusões O IDH pode influir na prevalência de DM2, embora a relação dependa de cada país, região e ano analisados.