Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID.

Background: Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology. Methods: In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination. Results: Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-ß and CNTF, among soluble analytes. Conclusions: Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.

Acute pesticide poisoning: Comparison of epidemiological characteristics between the rural and urban population

Objective: To analyze the behavior of pesticide poisoning associated with lethality in rural and urban populations in Colombia from 2007 to 2017. Methodology: Retrospective observational study that included a descriptive cross-sectional study and an ecological design that analyzed aggregate measures of morbidity, mortality, and risk attributable to the population in rural and urban areas. In the cross-sectional study, the relative risk was estimated to measure the factors associated with lethality among intoxications using Poisson regression with logarithmic function. For the time series, the trends were established with simple linear regression, and the seasonal decomposition was performed using the multiplicative model. Autocorrelations were tested using the Box-Ljung statistic. Results: Between 2007-2017; 89 490 cases were reported. The Morbidity due to poisoning showed a higher proportion in the rural population 36.03 cases per 100 000; this indicator was three times higher than in urban areas (12.33 cases per 100 000). The mortality rates in rural and urban areas were 1.00 and 0.13 cases per 100 000, respectively. The relative risk of fatality in case of intoxication was associated with the intention of suicide in the rural population Relative Risk (RR): 5.9 (95% CI: 5.0-6.9). Conclusion: A higher proportion of lethality associated with these events occurred in populations living in rural areas and reporting cases of suicidal intent. In addition, morbidity and mortality due to pesticide poisoning had the highest proportion in rural areas and a growing trend over time.

Objetivo: Analizar el comportamiento de las intoxicaciones por plaguicidas en poblaciones rurales y urbanas asociadas a la letalidad en Colombia durante 2007-2017. Metodología: Estudio observacional retrospectivo que incluyó: un estudio descriptivo transversal y un diseño ecológico que analizó medidas agregadas de morbilidad, mortalidad y riesgo atribuibles a la población en áreas rurales y urbanas. En el estudio transversal se estimó el riesgo relativo para medir los factores asociados a la letalidad entre las intoxicaciones mediante regresión de Poisson con función logarítmica. Para la serie de tiempo, las tendencias se establecieron con regresión lineal simple y la descomposición estacional se realizó mediante el modelo multiplicativo. Las autocorrelaciones se probaron mediante el estadístico Box-Ljung. Resultados: Entre 2007-2017; Se notificaron 89 490 casos. La Morbilidad por intoxicación presentó mayor proporción en la población rural 36,03 casos por 100 000; este indicador fue tres veces mayor que en las áreas urbanas (12,33 casos por 100 000). Las tasas de mortalidad en el área rural y urbana fueron de 1,00 y 0,13 casos por 100 000, respectivamente. El riesgo relativo de fatalidad en caso de intoxicación se asoció con la intención de suicidio en la población rural RR: 5,9 (IC 95%: 5,0-6,9). Conclusión: Una mayor proporción de letalidad asociada a estos eventos ocurrió en poblaciones que viven en áreas rurales y reportan casos de intención suicida. Además, la morbilidad y mortalidad por intoxicación por plaguicidas tuvo la mayor proporción en las zonas rurales y una tendencia creciente en el tiempo.

Objetivo: Analisar o comportamento das intoxicações por agrotóxicos em populações rurais e urbanas associadas à letalidade na Colômbia durante 2007-2017. Metodologia: Estudo observacional retrospectivo que incluiu: estudo transversal descritivo e delineamento ecológico que analisou medidas agregadas de morbidade, mortalidade e risco atribuíveis à população em áreas rurais e urbanas. No estudo transversal, o risco relativo foi estimado para medir os fatores associados à letalidade entre as intoxicações por meio da regressão de Poisson com função logarítmica. Para as séries temporais, as tendências foram estabelecidas com regressão linear simples e a decomposição sazonal foi realizada usando o modelo multiplicativo. As autocorrelações foram testadas usando a estatística Box-Ljung. Resultados: Entre 2007-2017; 89.490 casos foram notificados. A Morbidade por intoxicação apresentou maior proporção na população rural 36,03 casos por 100.000; este indicador foi três vezes superior ao das zonas urbanas (12,33 casos por 100 000). As taxas de mortalidade nas áreas rural e urbana foram de 1,00 e 0,13 casos por 100.000 habitantes, respectivamente. O risco relativo de fatalidade em caso de intoxicação associou-se à intenção de suicídio na população rural RR: 5,9 (IC 95%: 5,0-6,9). Conclusão: Maior proporção de letalidade associada a esses eventos ocorreu em populações residentes em áreas rurais e com relato de casos de intenção suicida. Além disso, a morbimortalidade por intoxicação por agrotóxicos teve maior proporção na zona rural e tendência crescente ao longo do tempo.

Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection.

Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) complexes, promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and represent host-directed therapeutic targets. The catalytic activity of SMARCA4 is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, ACE2 expression and virus susceptibility. The transcription factors HNF1A/B interact with and recruit mSWI/SNF complexes to ACE2 enhancers, which contain high HNF1A motif density. Notably, small-molecule mSWI/SNF ATPase inhibitors or degraders abrogate angiotensin-converting enzyme 2 (ACE2) expression and confer resistance to SARS-CoV-2 variants and a remdesivir-resistant virus in three cell lines and three primary human cell types, including airway epithelial cells, by up to 5 logs. These data highlight the role of mSWI/SNF complex activities in conferring SARS-CoV-2 susceptibility and identify a potential class of broad-acting antivirals to combat emerging coronaviruses and drug-resistant variants.

Evidencia de la efectividad del uso de aparatología ortopédica prequirúrgica en pacientes con labio y paladar hendido: revisión sistemática / Evidence of the effectiveness of the use of presurgical orthopedic appliances in patients with cleft lip and palate: a systematic review

Resumen El objetivo de este artículo fue evaluar la evidencia sobre el uso de una aparatología ortopédica prequirúrgica (AOP) en pacientes con labio y paladar hendido. Se realizó una búsqueda en las siguientes bases de datos: Medline/PubMed, Google Scholar, Clinical Trails.gov, ProQuest y Web of Science. En la búsqueda, se encontraron 7.926 registros, de los cuales se analizaron 105 artículos de texto completo; de éstos se incluyeron 23 estudios en pacientes con uso de AOP, asi como su grupo control sin el uso del AOP, previo al mismo tipo de cirugía. Los aparatos más utilizados para la AOP en el manejo de LPH fueron: el paladar pasivo (Paladar de Hotz), el modelador nasolaveolar (NAM), aparato McNeil y por último el T-traction; los principales desenlaces evaluados fueron: la estética facial y apariencia nasal; la evaluación de medidas cefalométricas, de vías aéreas superiores, nasales, del ancho de la fisura y así como puntos de referencia anatómicos como la distancia inter-canina e inter-tuberosidad. Además, se encontraron estudios que evaluaron oclusión y la fonación. La evidencia de esta literatura sugiere que el uso de aparatos activos tiene un mejor efecto que la placa pasiva, en términos de estética facial y aproximación de los segmentos maxilares para el cierre de la fisura. Sin embargo, la heterogeneidad, el riesgo de sesgo y la baja calidad de los estudios no permite tener conclusiones sólidas.

Abstract This review article aimed to evaluate the evidence on the use of a presurgical orthopedic appliance (POP) in patients with cleft lip and palate. The search was conducted using Medline/PubMed, Scholar Google, Clinical Trails, ProQuest, Scopus, and Web of Science databases. During the search, 7,926 records were found, of which 105 full-text articles were analyzed, and 23 studies included analysis in patients with the use of POP, and their control groups without the use of POP prior to the same type of surgery. The devices most used for POP in the management of LPH were: the passive palate (Hotz palate), the nasolaveolar moulding (NAM), the McNeil device, and finally, the T-traction. The primary outcomes evaluated were: facial aesthetics and nasal appearance; the evaluation of cephalometric measurements, upper airways, nasal fissure width, as well as anatomical references such as inter-canine and intertuberosity distances. In addition, studies that evaluated occlusion and phonation were found. The evidence from this literature suggests that the use of active appliances had a better effect than passive appliances in terms of facial aesthetics and approximation of the maxillary segments for the closure of the fissure. However, the heterogeneity, the risk of bias, and the low quality of the studies do not allow to state firm conclusions.

Accelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection.

The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.

Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for vaccines that not only prevent disease but also prevent transmission. Parenteral vaccines induce robust systemic immunity but poor immunity at the respiratory mucosa. We developed a vaccine strategy that we call "prime and spike," which leverages existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike boosters (spike). We show that prime and spike induces robust resident memory B and T cell responses, induces immunoglobulin A at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, prime and spike enables the induction of cross-reactive immunity against sarbecoviruses.

LRRC15 inhibits SARS-CoV-2 cellular entry in trans.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is mediated by the entry receptor angiotensin-converting enzyme 2 (ACE2). Although attachment factors and coreceptors facilitating entry are extensively studied, cellular entry factors inhibiting viral entry are largely unknown. Using a surfaceome CRISPR activation screen, we identified human LRRC15 as an inhibitory attachment factor for SARS-CoV-2 entry. LRRC15 directly binds to the receptor-binding domain (RBD) of spike protein with a moderate affinity and inhibits spike-mediated entry. Analysis of human lung single-cell RNA sequencing dataset reveals that expression of LRRC15 is primarily detected in fibroblasts and particularly enriched in pathological fibroblasts in COVID-19 patients. ACE2 and LRRC15 are not coexpressed in the same cell types in the lung. Strikingly, expression of LRRC15 in ACE2-negative cells blocks spike-mediated viral entry in ACE2+ cell in trans, suggesting a protective role of LRRC15 in a physiological context. Therefore, LRRC15 represents an inhibitory attachment factor for SARS-CoV-2 that regulates viral entry in trans.

Accelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection.

The chronic infection hypothesis for novel SARS-CoV-2 variant emergence is increasingly gaining credence following the appearance of Omicron. Here we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral loads. During the infection, we found an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately two-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution led to the emergence and persistence of at least three genetically distinct genotypes suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, using unique molecular indexes for accurate intrahost viral sequencing, we tracked the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, ultimately providing opportunity for the emergence of genetically divergent and potentially highly transmissible variants as seen with Delta and Omicron.

White Fibrous Papulosis of the Neck: A Case Report.

White fibrous papulosis of the neck is a rare entity, with a benign course and unknown pathogenesis. It is clinically characterized by the appearance of firm, persistent, usually asymptomatic, non-follicular papules located on the neck. We present the case of a 72-year-old patient who presented pruritic lesions on the neck whose biopsy was compatible with this entity.

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses.

As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin. ONE-SENTENCE SUMMARY: Broad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain.

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Longitudinal Immune Profiling of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection in a Solid Organ Transplant Recipient.

BACKGROUND: The underlying immunologic deficiencies enabling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for coronavirus disease 2019 (COVID-19). METHODS: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigations were performed on samples from the primary and secondary infections. RESULTS: Whole viral genome sequencing and phylogenetic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection. CONCLUSIONS: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naive CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ∼6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing.

Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a-o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H-chromenes 6a-h by a three-component reaction, and test these derivatives for anticancer and antifungal activity. Compounds 4a and 4b were more active than cisplatin (9) and topotecan (7) in SK-LU-1 cells, and more active than 9 in PC-3 cells. An evaluation was also made of the series of compounds 4 and 6 as potential antifungal agents against six Candida strains, finding their MIC50 to be less than or equal to that of fluconazole (8). Molecular docking studies are herein reported, for the interaction of 4 and 6 with topoisomerase IB and the active site of CYP51 of Candida spp. Compounds 4a-o and 6a-h interacted in a similar way as 7 with key amino acids of the active site of topoisomerase IB and showed better binding energy than 8 at the active site of CYP51. Hence, 4a-o and 6a-h are good candidates for further research, having demonstrated their dual inhibition of enzymes that participate in the growth of cancer and fungal cells.

Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity.

The emergence of SARS-CoV-2 variants with mutations in major neutralizing antibody-binding sites can affect humoral immunity induced by infection or vaccination1-6. Here we analysed the development of anti-SARS-CoV-2 antibody and T cell responses in individuals who were previously infected (recovered) or uninfected (naive) and received mRNA vaccines to SARS-CoV-2. While individuals who were previously infected sustained higher antibody titres than individuals who were uninfected post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (for example, B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (for example, B.1.617.2). While both groups retained neutralization capacity against all variants, plasma from individuals who were previously infected and vaccinated displayed overall better neutralization capacity than plasma from individuals who were uninfected and also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the effect of emerging variants on antibody neutralizing activity.

Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.

Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient's immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.

Simultaneous biofiltration of H2S and NH3 using compost mixtures from lignocellulosic waste and chicken manure as packing material.

Biofiltration offers an efficient and economical alternative for the elimination of offensive odors caused by hydrogen sulfide, ammonia, and volatile organic compounds. Considering that packing materials affect the performance and represent the main installation cost, the purpose of this work was to evaluate the biofiltration of H2S and NH3 comparing three composted mixtures made from chicken manure and lignocellulosic residues (pruning waste, sugarcane bagasse, and rice husk) used as packing material. A range of gas concentrations similar to those of a municipal WWTP was used in the biofiltration of a contaminated stream performed on a laboratory scale. The results indicate that at low concentrations of H2S (6-36 ppm) and NH3 (0-1 ppm), the three biofilters showed 100% removal efficiency. Now, at the maximum levels of gas concentrations of H2S (250 ppm) and NH3 (19 ppm) while the removal efficiency of H2S remained higher than 90% in all cases, the removal efficiency of NH3 remained higher than 90% only in the sugarcane bagasse biofilter. Compost mixtures with sugarcane bagasse and rice husk are highly reliable as packing material for biofiltration at high concentration of H2S. Specifically, the sugarcane bagasse mixture had the highest removal efficiency (99% H2S and 95% NH3) and the highest elimination capacity (15 g H2S/m3h and 0.6 g NH3/m3h), making it a better option for the elimination of both gases. These results represent a contribution to the construction of a low-price elimination system of offensive odors in WTTPs and other industries.