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Plant viruses are naturally occurring nanoparticles and adjuvants that interact with the mammalian immune system. This property can be harnessed in vaccines and immunotherapy. We have previously demonstrated that intratumoral immunotherapy with cowpea mosaic virus (CPMV) stimulates systemic and durable antitumor immunity in mouse tumor models and canine cancer patients. Here we compared the antitumor efficacy of CPMV with potato virus X (PVX) using a mouse model B-cell lymphoma (A20 and BALB/c mice). Despite their diverse morphologies and physiochemical properties, both plant viruses elicited systemic and long-lasting antitumor immune memory, preventing the recurrence of A20 lymphoma in rechallenge experiments. Data indicate differences in the underlying mechanism: CPMV persists longer in the tumor microenvironment (TME) compared to PVX; CPMV is a potent and multivalent toll-like receptor (TLR) agonist (activating TLRs 2, 4 and 7) while PVX may only weakly engage with TLR7. While CPMV and PVX recruit myeloid cells (neutrophils)─CPMV also recruits macrophages. Data further indicate that antiviral T cells may play a role in antitumor efficacy in the case of CPMV immunotherapy, however this may not be the case for PVX. Regardless of the mechanism of action, both CPMV and PVX elicited a durable antitumor response against a B-cell lymphoma tumor model and thus are intratumoral immunotherapy candidates for clinical development.

Virus-like particles (VLPs) are naturally occurring delivery platforms with potential for mRNA vaccines that can be used as an alternative to lipid nanoparticles. Here we describe a self-amplifying mRNA vaccine based on tobacco mosaic virus (TMV) expressing a mutated E7 protein from human papillomavirus 16 (HPV16). E7 is an early gene that plays a central role in viral replication and the oncogenic transformation of host cells, but nononcogenic mutant E7 proteins can suppress this activity. Immunization studies involving the delivery of self-amplifying mutant E7 mRNA packaged with TMV coat proteins confirmed the elicitation of E7-specific IgG antibodies. Additional in vitro splenocyte proliferation and cytokine profiling assays indicated the activation of humoral and cellular immune responses. We conclude that TMV particles are suitable for the delivery of mRNA vaccines and can preserve their integrity and functionality in vitro and in vivo .

In the Malveae tribe (Malvaceae), the axis supporting the flower has a joint at the upper third. This axis can be considered as an articulated pedicel, peduncle, peduncle-pedicel, or anthopodium. Such disparity in terminology reveals a duality in interpretation since this structure is classified as part of the inflorescence or part of the flower. In an effort to reach a consensus, this study aims to evaluate axes supporting the flowers of species from the Malveae tribe through ontogenetic, morphological, and histochemical analyses, using light microscopy and scanning electron microscopy. Ontogenetic analyses indicated that the axis supporting the flower is an articulated pedicel, which is divided into proximal and distal parts owing to the presence of the constriction (joint). Simultaneously, the articulated pedicel arises from the floral meristem, along with the establishment of the calyx and androecium. As development progresses, we observed frequent abscissions of the floral bud, along with the distal portion of the pedicel, at the joint. After this, the remaining proximal portion of the pedicel becomes secretory, as an extrafloral nectary, often foraged by ants of the genus Wasmannia. Thus, this ontogenetic analysis of the articulated pedicel helps in understanding its functionality and morphological variability, highlighting the importance of standardized terminology since it would lead to conceptual clarity in different studies. Additionally, this study, for the first time, reveals the presence of extrafloral nectaries on articulated pedicels in Malveae, a previously undocumented feature in Malveae and Malvaceae., (© 2024. The Author(s) under exclusive licence to The Botanical Society of Japan.)

Background/Objectives : For the development of new treatments, the acute phase of Chagas disease (CD) in experimental models acts as a filter to screen out potentially effective interventions. Therefore, the aim of this study was to evaluate ZnO nanocrystals and Ag-ZnO/AgO nanocomposites containing different proportions of silver (ZnO:5Ag, ZnO:9Ag and ZnO:11Ag) in an experimental model of the acute phase of CD. Methods : C57Bl/6 mice were infected with 1000 forms of the Colombian strain of T. cruzi . The treatment was carried out by gavage with 5 mg/kg/d for 7 consecutive days from the first detection of parasitemia. Weight, parasitemia and survival were assessed during treatment and up to the day of euthanasia. After euthanasia, the cardiac and intestinal parasitism, inflammatory infiltrate, collagen deposition and cytokine dosages were analyzed. Results : It was observed that the nanocomposites ZnO:9Ag and ZnO:11Ag were the most effective in reducing parasitemia and increasing the survival of the infected animals. However, pure ZnO induced the maintenance of parasitemia and reduced their survival. The ZnO:9Ag and ZnO:11Ag nanocomposites were able to reduce the number of cardiac amastigote nests. In addition, they were responsible for reducing TNF-α and IL-6 in situ. ZnO:9Ag and ZnO:11Ag induced a reduction in the intestinal inflammatory infiltrate and neuronal protection in the myenteric plexus, as well as reducing TNF-α in situ. Conclusions: Based on these results, it is suggested that there is an ideal concentration in terms of the proportion of Ag/AgO and ZnO in nanocomposites for use against CD. Thus, ZnO:9Ag or ZnO:11Ag nanomaterials are potential candidates for the development of new biotechnological products for the therapy of CD.

Cowpea mosaic virus (CPMV) is a plant virus that is currently being developed for intratumoral immunotherapy. CPMV relieves the immune system from tumor-induced immunosuppression; reprograms the tumor microenvironment to an activated state whereby the treated and distant tumors are recognized and eradicated. Toward translational studies, we investigated the safety of CPMV, specifically addressing whether pathogenicity would be induced in mammalian cells. We show that murine macrophage immune cells recognize CPMV; however, there is no indication of de novo viral protein synthesis or RNA replication. Furthermore, we show that CPMV does not induce hemolysis, platelet aggregation and plasma coagulation amongst other assays in human blood and immune cells. Taken together, we anticipate that these results will reinforce the development of CPMV as an immunotherapeutic platform., (© 2024. The Author(s).)

Neoadjuvant intratumoral (IT) therapy could amplify the weak responses to checkpoint blockade therapy observed in breast cancer (BC). In this study, we administered neoadjuvant IT anti-canine PD-1 therapy (IT acPD-1) alone or combined with IT cowpea mosaic virus therapy (IT CPMV/acPD-1) to companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. CMC patients treated weekly with acPD-1 (n = 3) or CPMV/acPD-1 (n = 3) for four weeks or with CPMV/acPD-1 (n = 3 patients not candidates for surgery) for up to 11 weeks did not experience immune-related adverse events. We found that acPD-1 and CPMV/acPD-1 injections resulted in tumor control and a reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of treated dogs. In two metastatic CMC patients, CPMV/acPD-1 treatments resulted in the control and reduction of established lung metastases. CPMV/acPD-1 treatments were associated with altered gene expression related to TLR1-4 signaling and complement pathways. These novel therapies could be effective for CMC patients. Owing to the extensive similarities between CMC and human BC, IT CPMV combined with approved anti-PD-1 therapies could be a novel and effective immunotherapy to treat local BC and suppress metastatic BC.

We present a computational model of networked neurons developed to study the effect of temperature on neuronal synchronization in the brain in association with seizures. The network consists of a set of chaotic bursting neurons surrounding a core tonic neuron in a square lattice with periodic boundary conditions. Each neuron is reciprocally coupled to its four nearest neighbors via temperature dependent gap junctions. Incorporating temperature in the gap junctions makes the coupling stronger when temperature rises, resulting in higher likelihood for synchrony in the network. Raising the temperature eventually makes the network elicit waves of synchronization in circular ripples that propagate from the center outwardly. We suggest this process as a possible underlying mechanism for seizures induced by elevated brain temperatures., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

This study proposes the was to evaluate the stability and methane production with organic load differents in an upflow anaerobic sludge blanket reactor (UASB) treating swine wastewater by methods of multivariate analysis. Four organic loads were used with average hydraulic holding times of one day. The methods of data analysis of linear regression, Pearson correlation, principal component analysis and hierarchical clustering analysis were used for understanding stability and methane production in the reactor. The highest concentrations of bicarbonate alkalinity of 683 mg L -1 CaCO 3 and total volatile acids of 1418 mg L -1 HAc with maximum organic loading applied were obtained. The optimal stability conditions occurred at an intermediate and partial alkalinity ratio between 0.24 and 0.25 observed in initial phases with a chemical oxygen demand (COD) removal of 47-57%. Maximum methane production was 9.0 L CH 4 d -1 observed with linear regression positive and occurred at the highest applied organic load, corresponding to the highest COD removal efficiency and increased microbial biomass. Positive and negative correlation between functional stability in anaerobic digestion showed regular activity between acids, alkalinity and organic matter removal. This fact was also proven by the analysis of principal components that showed three components responsible for explaining 83.2% of the data variability, and the alkalinity, organic matter influent and organic acids had the greatest effects on the stability of the UASB reactor. Hierarchical clusters detected the formation of five groupings with a similarity of 50.1%, indicating that temperature and pH were variables with unitary influences on data dimensionality., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The global economic downturn due to the COVID-19 pandemic, war in Ukraine, and worldwide inflation surge may have a profound impact on poverty-related infectious diseases, especially in low-and middle-income countries (LMICs). In this work, we developed mathematical models for HIV/AIDS and Tuberculosis (TB) in Brazil, one of the largest and most unequal LMICs, incorporating poverty rates and temporal dynamics to evaluate and forecast the impact of the increase in poverty due to the economic crisis, and estimate the mitigation effects of alternative poverty-reduction policies on the incidence and mortality from AIDS and TB up to 2030. Three main intervention scenarios were simulated-an economic crisis followed by the implementation of social protection policies with none, moderate, or strong coverage-evaluating the incidence and mortality from AIDS and TB. Without social protection policies to mitigate the impact of the economic crisis, the burden of HIV/AIDS and TB would be significantly larger over the next decade, being responsible in 2030 for an incidence 13% (95% CI 4-31%) and mortality 21% (95% CI 12-34%) higher for HIV/AIDS, and an incidence 16% (95% CI 10-25%) and mortality 22% (95% CI 15-31%) higher for TB, if compared with a scenario of moderate social protection. These differences would be significantly larger if compared with a scenario of strong social protection, resulting in more than 230,000 cases and 34,000 deaths from AIDS and TB averted over the next decade in Brazil. Using a comprehensive approach, that integrated economic forecasting with mathematical and epidemiological models, we were able to show the importance of implementing robust social protection policies to avert a significant increase in incidence and mortality from AIDS and TB during the current global economic downturn., (© 2024. The Author(s).)

Zinc oxide nanoparticles (ZnO NPs) are metal oxide nanomaterials, which are important for several applications: antibacterial, anthelmintic, antiprotozoal and antitumoral, among others. These applications are mainly related to the ability to spontaneously produce and induce the production of reactive oxygen species that are important components for the destruction of pathogens and tumor cells. While trying to potentiate ZnO NPs, studies have associated these NPs with silver oxide (AgO) or silver (Ag) NPs. It has already been reported that this combination (Ag-ZnO/AgO NPs) is able to enhance the microbicidal potential. Although possessing much potential for several purposes, it is important to evaluate whether this association also poses the risk of toxicity to cells and experimental models. Therefore, this work aimed to evaluate the toxicity of various Ag-ZnO/AgO NP nanocomposites, in vitro and in vivo. Accordingly, ZnO nanocrystals and nanocomposites with various concentrations of AgO (ZnO:5Ag, ZnO:9Ag or ZnO:11Ag) were used in different cytotoxicity models: Galleria mellonella ( G. mellonella ), cell lines (VERO and RAW 264.7) and C57BL/6 mice. In the G. mellonella model, four concentrations were used in a single dose, with subsequent evaluation of mortality. In the case of cells, serial concentrations starting at 125 µg/mL were used, with subsequent cytotoxicity assessment. Based on the safe doses obtained in G. mellonella and cell models, the best doses were used in mice, with subsequent evaluations of weight, biochemistry as also renal and liver histopathology. It was observed that the toxicity, although low, of the nanocomposites was dependent upon the concentration of AgO used in association with ZnO NPs, both in vitro and in vivo.

DEAD-box helicases are global regulators of liquid-liquid phase separation (LLPS), a process that assembles membraneless organelles inside cells. An outstanding member of the DEAD-box family is DDX3X, a multi-functional protein that plays critical roles in RNA metabolism, including RNA transcription, splicing, nucleocytoplasmic export, and translation. The diverse functions of DDX3X result from its ability to bind and remodel RNA in an ATP-dependent manner. This capacity enables the protein to act as an RNA chaperone and an RNA helicase, regulating ribonucleoprotein complex assembly. DDX3X and its orthologs from mouse, yeast (Ded1), and C. elegans (LAF-1) can undergo LLPS, driving the formation of neuronal granules, stress granules, processing bodies or P-granules. DDX3X has been related to several human conditions, including neurodevelopmental disorders, such as intellectual disability and autism spectrum disorder. Although the research into the pathogenesis of aberrant biomolecular condensation in neurodegenerative diseases is increasing rapidly, the role of LLPS in neurodevelopmental disorders is underexplored. This review summarizes current findings relevant for DDX3X phase separation in neurodevelopment and examines how disturbances in the LLPS process can be related to neurodevelopmental disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Juliana Ferreira de Oliveira reports financial support was provided by The São Paulo Research Foundation - FAPESP. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Due to the increasing incidence of cancer, there is a need to develop new platforms that can combat this disease. Cancer immunotherapy is a platform that takes advantage of the immune system to recognize and eradicate tumors and metastases. Our lab has identified a plant virus nanoparticle, cowpea mosaic virus (CPMV) as a promising approach for cancer immunotherapy. When administered intratumorally, CPMV relieves the immune system of tumor-induced immunosuppression and reprograms the tumor microenvironment into an activated state to launch systemic antitumor immunity. The efficacy of CPMV has been tested in many tumor models and in canine cancer patients with promising results: tumor shrinkage, systemic efficacy (abscopal effect), and immune memory to prevent recurrence. To translate this drug candidate from the bench to the clinic, studies that investigate the safety, pharmacology, and toxicity are needed. In this work, we describe the efficacy of CPMV against a metastatic ovarian tumor model and investigate the biodistribution of CPMV after single or repeated intraperitoneal administration in tumor-bearing and healthy mice. CPMV shows good retention in the tumor nodules and broad bioavailability with no apparent organ toxicity based on histopathology. Data indicate persistence of the viral RNA, which remains detectable 2 weeks post final administration, a phenomenon also observed with some mammalian viral infections. Lastly, while protein was not detected in stool or urine, RNA was shed through excretion from mice; however, there was no evidence that RNA was infectious to plants. Taken together, the data indicate that systemic administration results in broad bioavailability with no apparent toxicity. While RNA is shed from the subjects, data suggest agronomical safety. This data is consistent with prior reports and provides support for translational efforts., Competing Interests: The authors declare the following competing financial interest(s): N.F.S. is a co-founder of, has equity in, and has a financial interest with Mosaic ImmunoEnginering Inc. and is a co-founder and serves as manager of Pokometz Scientific LLC, under which she is a paid consultant to Mosaic ImmunoEngineering Inc., Flagship Labs 95 Inc., and Arana Biosciences Inc., (© 2024 American Chemical Society.)

Globally, millions of lives are impacted every year by infectious diseases outbreaks. Comprehensive and innovative surveillance strategies aiming at early alert and timely containment of emerging and reemerging pathogens are a pressing priority. Shortcomings and delays in current pathogen surveillance practices further disturbed informing responses, interventions, and mitigation of recent pandemics, including H1N1 influenza and SARS-CoV-2. We present the design principles of the architecture for an early-alert surveillance system that leverages the vast available data landscape, including syndromic data from primary health care, drug sales, and rumors from the lay media and social media to identify areas with an increased number of cases of respiratory disease. In these potentially affected areas, an intensive and fast sample collection and advanced high-throughput genome sequencing analyses would inform on circulating known or novel pathogens by metagenomics-enabled pathogen characterization. Concurrently, the integration of bioclimatic and socioeconomic data, as well as transportation and mobility network data, into a data analytics platform, coupled with advanced mathematical modeling using artificial intelligence or machine learning, will enable more accurate estimation of outbreak spread risk. Such an approach aims to readily identify and characterize regions in the early stages of an outbreak development, as well as model risk and patterns of spread, informing targeted mitigation and control measures. A fully operational system must integrate diverse and robust data streams to translate data into actionable intelligence and actions, ultimately paving the way toward constructing next-generation surveillance systems., (©Pablo Ivan P Ramos, Izabel Marcilio, Ana I Bento, Gerson O Penna, Juliane F de Oliveira, Ricardo Khouri, Roberto F S Andrade, Roberto P Carreiro, Vinicius de A Oliveira, Luiz Augusto C Galvão, Luiz Landau, Mauricio L Barreto, Kay van der Horst, Manoel Barral-Netto, ÆSOP Collaborating Teams. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 09.01.2024.)

Four new nitrogen-containing heterocyclic derivatives (acridine, quinoline, indole, pyridine) were synthesized and their biological properties were evaluated. The compounds showed affinity for DNA and HSA, with CAIC and CAAC displaying higher binding constants (Kb) of 9.54 × 10 4 and 1.06 × 10 6 , respectively. The fluorescence quenching assay (Ksv) revealed suppression values ranging from 0.34 to 0.64 × 10 3  M -1 for ethidium bromide (EB) and 0.1 to 0.34 × 10 3  M -1 for acridine orange (AO). Molecular docking confirmed the competition of the derivatives with intercalation probes at the same binding site. At 10 μM concentrations, the derivatives inhibited topoisomerase IIα activity. In the antiproliferative assays, the compounds demonstrated activity against MCF-7 and T47-D tumor cells and nonhemolytic profile. Regarding toxicity, no acute effects were observed in the embryos. However, some compounds caused enzymatic and cardiac changes, particularly the CAIC, which increased SOD activity and altered heart rate compared to the control. These findings suggest potential antitumor action of the derivatives and indicate that substituting the acridine core with different cores does not interfere with their interaction and topoisomerase inhibition. Further investigations are required to assess possible toxicological effects, including reactive oxygen species generation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The lack of optimal models to evaluate novel agents is delaying the development of effective immunotherapies against human breast cancer (BC). In this prospective open label study, we applied neoadjuvant intratumoral immunotherapy with empty cowpea mosaic virus-like particles (eCPMV) to 11 companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. We found that two neoadjuvant intratumoral eCPMV injections resulted in tumor reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of injected dogs. Tumor reduction was independent of clinical stage, tumor size, histopathologic grade, and tumor molecular subtype. RNA-seq-based analysis of injected tumors indicated a decrease in DNA replication activity and an increase in activated dendritic cell infiltration in the tumor microenvironment. Immunohistochemistry analysis demonstrated significant intratumoral increases in neutrophils, T and B lymphocytes, and plasma cells. eCPMV intratumoral immunotherapy demonstrated antitumor efficacy without any adverse effects. This novel immunotherapy has the potential for improving outcomes for human BC patients.

Background: Despite the benefits of breastfeeding, early weaning is a reality, so less than 50% of children worldwide and in Brazil are on exclusive breastfeeding in the sixth month of life. A strategy to counteract this scenario is breastfeeding counseling. This study aims to verify the effectiveness of individualized counseling by nurses trained in breastfeeding counseling, on the duration of exclusive breastfeeding, compared to standard care., Methods: Multicenter, randomized, parallel, and open clinical trial, with primiparous women aged over 18 years, hospitalized in rooming-in wards at participating centers and hemodynamically stable, aware, and oriented, who had a single-fetus pregnancy and gave birth, regardless of the type of delivery, with live child, gestational age of 37 to 42 weeks and birth weight greater than 2500 g. The women will be initially approached in rooming-in wards and, upon consent to participate in the study, will be allocated through randomization by blocks composed of eight participants in two groups: intervention and control. The randomization lists will be organized by a central without involvement with the study, which will manage the allocation groups and be prepared in the Randon® program. Women allocated to the intervention group will receive breastfeeding counseling by trained nurses, and those in the control group will receive standard care at the center participating in the study., Discussion: The results can contribute to breastfeeding by evidencing possible exclusivity and duration of the counseling trained nurses provide., Trial Registration: REBEC RBR-4w9v5rq (UTN: U1111-1284-3559) ( https://ensaiosclinicos.gov.br/rg/RBR-4w9v5rq ). Posted on March 20, 2023., (© 2023. The Author(s).)

Introduction: Housing-related factors can be predictors of health, including of diabetes outcomes. We analysed the association between subsidised housing residency and diabetes mortality among a large cohort of low-income adults in Brazil., Research Design and Methods: A cohort of 9 961 271 low-income adults, observed from January 2010 to December 2015, was created from Brazilian administrative records of social programmes and death certificates. We analysed the association between subsidised housing residency and time to diabetes mortality using a Cox model with inverse probability of treatment weighting and regression adjustment. We assessed inequalities in this association by groups of municipality Human Development Index. Diabetes mortality included diabetes both as the underlying or a contributory cause of death., Results: At baseline, the mean age of the cohort was 40.3 years (SD 15.6 years), with a majority of women (58.4%). During 29 238 920 person-years of follow-up, there were 18 775 deaths with diabetes as the underlying or a contributory cause. 340 683 participants (3.4% of the cohort) received subsidised housing. Subsidised housing residents had a higher hazard of diabetes mortality compared with non-residents (HR 1.17; 95% CI 1.05 to 1.31). The magnitude of this association was more pronounced among participants living in municipalities with lower Human Development Index (HR 1.30; 95% CI 1.04 to 1.62)., Conclusions: Subsidised housing residents had a greater risk of diabetes mortality, particularly those living in low socioeconomic status municipalities. This finding suggests the need to intensify diabetes prevention and control actions and prompt treatment of the diabetes complications among subsidised housing residents, particularly among those living in low socioeconomic status municipalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The COVID-19 pandemic caused by SARS-CoV-2 sparked intensive research into the development of effective vaccines, 50 of which have been approved thus far, including the novel mRNA-based vaccines developed by Pfizer and Moderna. Although limiting the severity of the disease, the mRNA-based vaccines presented drawbacks, such as the cold chain requirement. Moreover, antibody levels generated by these vaccines decline significantly after 6 months. These vaccines deliver mRNA encoding the full-length spike (S) glycoprotein of SARS-CoV-2, but must be updated as new strains and variants of concern emerge, creating a demand for adjusted formulations and booster campaigns. To overcome these challenges, we have developed COVID-19 vaccine candidates based on the highly conserved SARS CoV-2, 809-826 B-cell peptide epitope (denoted 826) conjugated to cowpea mosaic virus (CPMV) nanoparticles and bacteriophage Qβ virus-like particles, both platforms have exceptional thermal stability and facilitate epitope delivery with inbuilt adjuvant activity. We evaluated two administration methods: subcutaneous injection and an implantable polymeric scaffold. Mice received a prime-boost regimen of 100 μg per dose (2 weeks apart) or a single dose of 200 μg administered as a liquid formulation, or a polymer implant. Antibody titers were evaluated longitudinally over 50 weeks. The vaccine candidates generally elicited an early Th2-biased immune response, which stimulates the production of SARS-CoV-2 neutralizing antibodies, followed by a switch to a Th1-biased response for most formulations. Exceptionally, vaccine candidate 826-CPMV (administered as prime-boost, soluble injection) elicited a balanced Th1/Th2 immune response, which is necessary to prevent pulmonary immunopathology associated with Th2 bias extremes. While the Qβ-based vaccine elicited overall higher antibody titers, the CPMV-induced antibodies had higher avidity. Regardless of the administration route and formulation, our vaccine candidates maintained high antibody titers for more than 50 weeks, confirming a potent and durable immune response against SARS-CoV-2 even after a single dose., Competing Interests: NFS is a co-founder of, has equity in, and has a financial interest with Mosaic ImmunoEngineering Inc. NFS serves as Director, Board Member, and Acting Chief Scientific Officer, and paid consultant to Mosaic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Affonso de Oliveira, Zhao, Xiang, Shin, Villaseñor, Deng, Shukla, Chen and Steinmetz.)

Background and Aims: Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host immune response to an infection. Curcumin is a yellow polyphenol derived from the rhizome of Curcuma longa with anti-inflammatory and antioxidant properties scientifically proven, a condition that allowed its use as a tool in the treatment of sepsis. Thus, the purpose of this article was to systematically review the evidence on the impact of curcumin's anti-inflammatory effect on experimental sepsis., Methods: For this, the PubMed, MEDLINE, EMBASE, Scopus, Web of Science, and LILACS databases were used, and the research was not limited to a specific publication period. Only original articles in English using in vivo experimental models (rats or mice) of sepsis induction performed by administration of lipopolysaccharide (LPS) or cecal ligation and perforation surgery (CLP) were included in the study. Studies using curcumin in dry extract or with a high degree of purity were included. At initial screening, 546 articles were selected, and of these, 223 were eligible for primary evaluation. Finally, 12 articles with full text met all inclusion criteria. Our results showed that curcumin may inhibit sepsis-induced complications such as brain, heart, liver, lungs, and kidney damage. Curcumin can inhibit inflammatory factors, prevent oxidative stress, and regulate immune responses in sepsis. Additionally, curcumin increased significantly the survival rates after experimental sepsis in several studies. The modulation of the immune response and mortality by curcumin reinforces its protective effect on sepsis and indicates a potential therapeutic tool for the treatment of sepsis., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2023 Barbara Martins Vieira et al.)

The fruits of palm trees (Arecaceae) are a very important food source for fauna and for humans, despite the still incipient role of these fruits in conventional diet. Seven palm tree species (plus one variety) that are native to the southern half of South America located east of the Andes (Argentina, Paraguay, Uruguay, and the southern states of Brazil) were studied. For the first time, the fatty acid profiles of palm seeds and the content of both amino acids and phenolic compounds present in the pulp (yellowish fleshy mesocarps) of the fruits were determined. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to screen and quantify thirty-two phenols and HPLC was used to determine the amino acid contents and fatty acids profiles of the species. Twenty-five percent of the fatty acids in the seeds of B. lallemantii, Butia odorata (var. pulposa), B. witeckii, and Syagrus romanzoffiana were found to be unsaturated. One species (B. lallemantii) had a high and well-balanced amino acid content (28,900 mg/kg), while six species (B. odorata, B. catarinensis, B. witeckii, Euterpe edulis, and Syagrus romanzoffiana) contained more than 14,000 mg/kg of amino acids. A high content of the phenolic compounds ferulic acid, luteolin, quercetin-3-rutinoside, isoquercetin, and isorhamnetin were found in many species, most notably in B. odorata, B. catarinensis, and B. witeckii., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To classify the most up-to-date factors associated with COVID-19 disease outcomes in Brazil., Design: Retrospective study., Setting: Nationwide Brazilian COVID-19 healthcare registers., Participants: We used healthcare data of individuals diagnosed with mild/moderate (n=70 056 602) or severe (n=2801 380) COVID-19 disease in Brazil between 26 February 2020 and 15 November 2021., Main Outcome Measures: Risk of hospitalisation and mortality affected by demographic, clinical and socioeconomic variables were estimated. The impacts of socioeconomic inequalities on vaccination rates, cases and deaths were also evaluated., Results: 15.6 million SARS-CoV-2 infection cases and 584 761 COVID-19-related deaths occurred in Brazil between 26 February 2020 and 15 November 2021. Overall, men presented a higher odds of death than women (OR=1.14, 95% CI 1.13 to 1.15), but postpartum patients admitted to hospital wards were at increased odds of dying (OR=1.23, 95% CI 1.13 to 1.34) compared with individuals without reported comorbidities. Death in younger age groups was notably higher in most deprived municipalities and also among individuals <40 years belonging to indigenous backgrounds compared with white patients, as shown by descriptive analysis. Ethnic/racial backgrounds exhibited a continuum of decreasing survival chances of mixed-race (OR=1.11, 95% CI 1.10 to 1.12), black (OR=1.34, 95% CI 1.32 to 1.36) and indigenous (OR=1.42, 95% CI 1.31 to 1.54) individuals, while those in most deprived municipalities also presented an increased odds of death (OR=1.38, 95% CI 1.36 to 1.40). Deprivation levels also affect the prompt referral of patients to adequate care. Our results show that the odds of death of individuals hospitalised for less than 4 days is more than double that of patients with close-to-average hospital stays (OR=2.07, 95% CI 2.05 to 2.10). Finally, negative vaccination status also increased the odds of dying from the disease (OR=1.29, 95% CI 1.28 to 1.31)., Conclusions: The data provide evidence that the patterns of COVID-19 mortality in Brazil are influenced by both individual-level health and social risk factors, as well as municipality-level deprivation. In addition, these data suggest that there may be inequalities in the timely provision of appropriate healthcare that are related to municipality-level deprivation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a highly potent, systemic, and durable antitumor immune response against the treated and untreated, distant metastatic sites (abscopal effect). Potent efficacy was demonstrated in multiple tumor mouse models and, most importantly, in canine cancer patients with spontaneous tumors. Data indicate that presence of anti-CPMV antibodies are not neutralizing and that in fact opsonization leads to enhanced efficacy. Plant viruses are part of the food chain, but to date, there is no information on human exposure to CPMV. Therefore, patient sera were tested for the presence of immunoglobulins against CPMV, and indeed, >50% of deidentified patient samples tested positive for CPMV antibodies. To get a broader sense of plant virus exposure and immunogenicity in humans, we also tested sera for antibodies against tobacco mosaic virus (>90% patients tested positive), potato virus X (<20% patients tested positive), and cowpea chlorotic mottle virus (no antibodies were detected). Further, patient sera were analyzed for the presence of antibodies against the coliphage Qβ, a platform technology currently undergoing clinical trials for in situ vaccination; we found that 60% of patients present with anti-Qβ antibodies. Thus, data indicate human exposure to CPMV and other plant viruses and phages. Next, we thought to address agronomical safety; i.e., we examined the fate of CPMV after intratumoral treatment and oral gavage (to mimic consumption by food). Because live CPMV is used, an important question is whether there is any evidence of shedding of infectious particles from mice or patients. CPMV is noninfectious toward mammals; however, it is infectious toward plants including black-eyed peas and other legumes. Biodistribution data in tumor-bearing and healthy mice indicate little leaching from tumors and clearance via the reticuloendothelial system followed by biliary excretion. While there was evidence of shedding of RNA in stool, there was no evidence of infectious particles when plants were challenged with stool extracts, thus indicating agronomical safety. Together these data aid the translational development of CPMV as a drug candidate for cancer immunotherapy.

Schistosomiasis is a neglected disease that affects about 258 million people worldwide. Caused by Schistosoma mansoni, helminth which, in Brazil, it is present on 19 states and capital. Praziquantel (PZQ) treatment presents low efficacy and adverse effects in parasites juvenile stages. Thiosemicarbazones and thiazolidinones are rising as potent chemical groups that have biological activity wide spectrum, and with radical modifications, they may become more effective and selective. Aiming to evaluate the action of these molecules against S. mansoni, JF series thiosemicarbazones and thiazolidinones (LqIT/UFPE) were synthesized: JF30, JF31, JF33, JF34, JF35, JF36, JF38, JF39, JF42 and JF43. Several parameters were evaluated, such as: their cytotoxicity in VERO cells, in vitro schistosomicidal activity for juvenile and adult worms and their action on worms through ultrastructural changes. Cytotoxicity indices ranged from 272 µM to 725 µM. When evaluating mortality rate, adult and juvenile worms showed 100 % mortality rate within 24 h and 48 h, respectively, when exposed to the compounds JF31 and JF43 at a dose of 200 µM. Also, motility, mortality and oviposition parameters were evaluated: JF31 and JF43 presented a score of 0 in 24 h, meaning total absence of movement, whereas no eggs and soft tissue damage were observed under optical microscopy. Through scanning electron microscopy, integumentary alterations caused by the compounds JF31 and JF43 were observed, such as: exposure of the musculature, formation of integumentary bubbles, integuments with abnormal morphology and destruction of tubercles and spikes. The results shoerd that the compound JF31 was 2.39 times more selective for adult worms and JF43 was 3.74 times more selective for juvenile worms. Thus, the compounds JF43 and JF31 are the most promising for presenting schistosomicidal activity of S. mansoni., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Phishing is an attack characterized by attempted fraud against users. The attacker develops a malicious page that is a trusted environment, inducing its victims to submit sensitive data. There are several platforms, such as PhishTank and OpenPhish, that maintain databases on malicious pages to support anti-phishing solutions, such as, for example, block lists and machine learning. A problem with this scenario is that many of these databases are disorganized, inconsistent, and have some limitations regarding integrity and balance. In addition, because phishing is so volatile, considerable effort is put into preserving temporal information from each malicious page. To contribute, this article built a phishing database with consistent and balanced data, temporal information, and a significant number of occurrences, totaling 942,471 records over the 5 years between 2016 and 2021. Of these records, 135,542 preserve the page's source code, 258,416 have the attack target brand detected, 70,597 have the hosting service identified, and 15,008 have the shortener service discovered. Additionally, 123,285 records store WHOIS information of the domain registered in 2021. The data is available on the website https://piracema.io/repository., (© 2022. The Author(s).)

Objectives: COVID-19 has been associated with long-term consequences to patient wellness and quality of life. Data on post-COVID-19 conditions are scarce in developing countries. This study aimed to investigate long COVID in a cohort of hospitalized patients in Brazil., Methods: Surviving patients discharged from the hospital between July 1, 2020 and March 31, 2021 were assessed between 2 and 12 months after acute onset of COVID-19. The outcomes were the prevalence of persistent symptoms, risk factors associated with long COVID, and quality of life as assessed by the EuroQol 5D-3L questionnaire., Results: Of 439 participants, most (84%) reported at least one long COVID symptom, at a median of 138 days (interquartile range [IQR] 90-201) after disease onset. Fatigue (63.1%), dyspnea (53.7%), arthralgia (56.1%), and depression/anxiety (55.1%) were the most prevalent symptoms. In multivariate analysis, dysgeusia (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.18-3.44, P <0.001) and intensive care unit (ICU) admission (OR 2.6, 95% CI 1.19-6.56, P = 0.03) were independently associated with long COVID. Fifty percent of patients reported a worsened clinical condition and quality of life., Conclusion: Long-term outcomes of SARS-CoV-2 infection in a low- to middle-income country were relevant. Fatigue was the most common persistent symptom. ICU admission was an independent factor associated with long COVID. Dysgeusia could be a potential predictor of long COVID., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To analyze the coping strategies used by primary healthcare (PHC) professionals. Methods: A cross-sectional, descriptive-analytical study realized with professionals working in primary healthcare units in São José do Rio Preto, a large city in the interior of São Paulo, Brazil. For data collection, we used an instrument developed by the researchers containing sociodemographic and professional variables, as well as the Problem Coping Modes Scale (EMEP). Results: We evaluated 333 PHC professionals. A difference was observed between the scores of the four coping strategies (p < 0.001), with the highest score for the problem-focused strategy (3.8) and the lowest score for the emotion-focused strategy (2.4). Physicians had the lowest scores in coping strategies focused on religious practices/fantastical thinking (p < 0.001) and pursuit of social support (p = 0.045), while community health agents had the highest scores in these coping strategies. Conclusions: Professionals working in PHC have different coping strategies for the problems and stressful situations experienced in the work environment. These strategies can involve more positive attitudes focused on confrontation and problem solving, and on emotional responses that involve attitudes of avoidance and denial of the problem., Competing Interests: The authors declare no conflict of interest.

In Brazil, the horse is frequently used in cultural activities, sports, and in rural and urban work, implementing the economy in different social classes. Among the diseases in horses with zoonotic potential, rabies has been neglected in the country, increasing the risk of spreading the disease across borders. The present study evaluated the spatiotemporal distribution and temporal trend of rabies in horses in Brazil between 2010 and 2019. During this period, 1290 cases of rabies were detected in horses in Brazil, mainly in the states of São Paulo (21.7%) and Mato Grosso (13.3%). However, Espírito Santo stood out, with an incidence risk (IR) of 139.7 cases of rabies per 100,000 horses. The years 2013 and 2017 had higher peaks of IR for the disease, and the states that contributed to this increase were Mato Grosso, São Paulo, and Espírito Santo. There was no monthly seasonality of the disease among the states. The temporal trend revealed an increase for the northeastern region (Annual Percentage Change [APC]: 8.9%) and for Alagoas State (APC: 26.6%). In the spatiotemporal analysis, three high-risk clusters were formed: (i) cluster A (Relative Risk [RRs]: 6.21), involving only Minas Gerais, between 2017 and 2019; (ii) cluster B (RRs: 6.18), involving only Mato Grosso, between 2011 and 2013; and (iii) cluster C (RRs:4.71), involving the states of Rio de Janeiro and Espírito Santo, between 2010 and 2014. Only the states of Roraima and Amapá had no cases of equine rabies during the study period. Therefore, rabies in horses occurs in all Brazilian regions, with areas at high risk of infection concentrated in the Southeast. However, attention should be directed to the north-eastern and northern states, where notifications were infrequent, with an unknown risk in relation to the spread of rabies to transboundary regions. This is the first study evaluating the interstate distribution of rabies in equine species in regions of Brazil., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Thiazolidine compounds NJ20 {(E)-2-(2-(5-bromo-2-methoxybenzylidene)hydrazinyl)-4-(4-nitrophenyl)thiazole} and NW05 [(2-(benzo (d) (1,3) dioxol-4-ylmethylene)-N-(4-bromophenyl)-thiosemicarbazone] potentiated the effect of norfloxacin in resistant bacteria; however, there are no reports on their effects on Nauphoeta cinerea in the literature. The objective of this work was to evaluate the behavioral effects and oxidative markers of NW05 and NJ20 in lobster cockroach N. cinerea . To evaluate the behavioral study, a video tracking software was used to evaluate the locomotor points and the exploratory profile of cockroaches in the horizontal and vertical regions of a new environment. The total concentration of thiol and reduced glutathione (GSH), substances reactive to thiobarbituric acid (TBARS), free iron (II) content and mitochondrial viability were determined. The antioxidant potential was evaluated by the DPPH method. Both substances induced changes in the behavior of cockroaches, showing a significant reduction in the total distance covered and in the speed. In the cell viability test (MTT), there was a significant reduction for NJ20 (1 mM). NJ20 caused a significant increase in total levels of thiol and non-protein thiol (NPSH), although it also slightly increased the content of malondialdehyde (MDA). Both compounds (NW05 and NJ20) caused a significant reduction in the content of free iron at a concentration of 10 mM. In conclusion, the compound NJ20 caused moderate neurotoxicity (1 mM), but had good antioxidant action, while NW05 did not show toxicity or significant antioxidant activity in the model organism tested. It is desirable to carry out complementary tests related to the antioxidant prospection of these same compounds, evaluating them at different concentrations.

Aim: The study aim was to map clinical characteristics and the evolution of pregnancies in pregnant women with confirmed diagnosis of SARS-CoV-2 infection., Methods: Searching four databases, studies were investigated that described the evolution of pregnancies in women diagnosed with SARS-CoV-2 infection through laboratory tests. A scoping review was undertaken, including 35 articles published in English. Two pairs of independent researchers synthesized the data., Results: Most studies were case studies or case series and had a low risk of bias. A predominance of cases was found in women over the age of 30 years who got infected in the third term of pregnancy and who had comorbidities. The prematurity index varied with the heterogeneity of the samples, and the cases of abortion occurred in combination with severe forms of infection. Caesarean section deliveries predominated, indicated mainly by respiratory decompensation caused by infection. Most women were discharged., Conclusion: Based on the reviewed studies, the profile and evolution of pregnant women infected with COVID-19 could be evaluated., (© 2021 John Wiley & Sons Australia, Ltd.)

The buffalo herds in Brazil have been an alternative for increasing the economy in different biomes. For this reason, knowledge of the spatial distribution of diseases of mandatory notification in buffalo herds, such as brucellosis and tuberculosis, is essential to guarantee the quality of exported animal products, as well as assist in strategies of national control and eradication programs. In the present study, we aimed to evaluate the spatiotemporal distribution and temporal trends of brucellosis and tuberculosis in buffalo in Brazilian states between 2012-2019. During this period, 474 cases of brucellosis and 604 cases of tuberculosis were observed in buffalo in Brazil, with no significant differences between the total number of cases and incidence risk. The spatial distribution for the states was mostly heterogeneous, showing similarities of occurrences for both diseases in the south, north, and the states of Minas Gerais and Pernambuco. In the eight years evaluated, tuberculosis showed cyclical variation every 1-2 years; however, for brucellosis, there was a cyclical trend only between 2012-2015, with a significant decrease until 2018. Among Brazilian states, Pará had greater disease case numbers, with 34 % for brucellosis and 40.6 % for tuberculosis. Temporal trend analysis showed an increase for Pernambuco (annual percentage change [APC]: 21.0 [CI = 20.3; 21.8]), Paraná (APC: 27.1 [CI = 5.6; 53.0]), and Santa Catarina (APC: 10.4 [CI = 0.8; 21.0]) for brucellosis, and for tuberculosis, only for Santa Catarina state (APC: 24.1 [CI = 15.5; 33.3]). Spatiotemporally, there were four high-risk brucellosis clusters with a primary cluster, cluster A (relative risk [RRs] = 53.42, P < 0.001), involving the state of Amazonas between 2014-2015. For tuberculosis, there were three states of high risk, with a primary cluster, cluster E (RRs = 28.18, P < 0.001), involving the states of Pará, Roraima, Amazonas, Rondônia, and Acre in 2014. In conclusion, brucellosis and tuberculosis in buffalo in Brazil are heterogeneously distributed, with well-defined regions of high historical risk of infection. Among these regions, the states of Amazonas, Pará, Amapá, and Minas Gerais stand out due to the higher risk of infection for both brucellosis and tuberculosis, alerting Brazilian authorities to the need for disease control actions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Current studies estimate that 1-3% of females with unexplained intellectual disability (ID) present de novo splice site, nonsense, frameshift, or missense mutations in the DDX3X protein (DEAD-Box Helicase 3 X-Linked). However, the cellular and molecular mechanisms by which DDX3X mutations impair brain development are not fully comprehended. Here, we show that the ID-linked missense mutation L556S renders DDX3X prone to aggregation. By using a combination of biophysical assays and imaging approaches, we demonstrate that this mutant assembles solid-like condensates and amyloid-like fibrils. Although we observed greatly reduced expression of the mutant allele in a patient who exhibits skewed X inactivation, this appears to be enough to sequestrate healthy proteins into solid-like ectopic granules, compromising cell function. Therefore, our data suggest ID-linked DDX3X L556S mutation as a disorder arising from protein misfolding and aggregation., Competing Interests: Nothing to disclose., (© 2021 The Author(s).)

Background: In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential., Methods: The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques., Results: An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC 50 of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC 50  > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability., Conclusions: These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.

The purpose of this study was to analyze the effects of the application of multivariate criteria of principal components and hierarchical clustering as a mechanism for monitoring the performance of Tifton 85 grass (Cynodon spp.) planted in horizontal subsurface flow constructed wetland reactor (HSSF-CW) under different organic (OLR), nutritional and sodium loads of swine wastewater (SW). The HSSF-CW planted with Tifton 85 grass was used as a swine wastewater after treatment applying organic loading rates between 26.1 (1st cut) and 360.6 kg ha -1 day -1 COD (8th cut). The maximum performances of HSSF-CW consisted of 52.0 t ha -1 of productivity and 24.0% of crude protein, with the application of 59.7, 64.2, and 31.2 kg ha -1 day -1 of TKN, P T , and K + , respectively. The eleven original variables generated four new components, with PC 4 accounting for 94.0% of total variance, a condition strengthened with four data groupings greater than 48% similarity and three data groupings greater than 95% similarity between the variables. There was a strong association between of nitrogen, phosphorus, and potassium concentration by the hierarchical grouping and the intermediate cuts and lower temperatures.

In this study, we report the synthesis of eight novel indole-thiazole and indole-thiazolidinone derivatives, as well as their ability to interact with DNA, analysed through the UV-vis absorption, fluorescence, circular dichroism (CD), viscosity techniques and molecular docking. The ctDNA interaction analysis demonstrated different spectroscopic effects and the affinity constants (Kb) calculated by the UV-vis absorption method were between 2.08 × 10 5 and 6.99 × 10 6  M -1 , whereas in the fluorescence suppression constants (Ksv) ranged between 0.38 and 0.77 × 10 4  M -1 and 0.60-7.59 × 10 4  M -1 using Ethidium Bromide (EB) and 4',6-Diamidino-2-phenylindole (DAPI) as fluorescent probes, respectively. Most derivatives did not alter significantly the secondary structure of the ctDNA according to the CD results. None of the compounds was able to change the relative viscosity of the ctDNA. These results prove that compounds interact with ctDNA via groove binding, which was confirmed by A-T rich oligonucleotide sequence assay with compound JF-252, suggesting the importance of both the phenyl ring coupled to C-4 thiazole ring and the bromo-unsubstituted indole nucleus., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Moderate to severe asthma could be induced by diverse proinflammatory cytokines, as IL-17 and IFN-γ, which are also related to treatment resistance and airway hyperresponsiveness. Oxazolidines emerged as a novel approach for asthma treatment, since some chemical peculiarities were suggested by previous studies., Objective: The present study aimed to evaluate the IL-17A and IFN-γ modulatory effect of two new oxazolidine derivatives (LPSF/NB-12 and -13) on mononucleated cells of patients with moderate and severe asthma., Methods: The study first looked at potential targets for oxazolidine derivatives using SWISS-ADME. After the synthesis of the compounds, cytotoxicity and cytokine levels were analyzed., Results: We demonstrated that LPSF/NB-12 and -13 reduced IFN-γ and IL-17 production in peripheral blood mononucleated cells from asthmatic patients in a concentrated manner. Our in silico analysis showed the neurokinin-1 receptor as a common target for both compounds, which is responsible for diverse proinflammatory effects of moderate and severe asthma., Conclusion: The work demonstrated a novel approach against asthma, which deserves further studies of its mechanisms of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The new Covid-19 pandemic has left traces of suffering and devastation to individuals of almost all countries worldwide and severe impact on the global economy. Understanding the clinical characteristics, interactions with the environment, and the variables that favor or hinder its dissemination help the public authorities in the fight and prevention, leading for a rapid response in society. Using models to estimate contamination scenarios in real time plays an important role. Population compartments models based on ordinary differential equations (ODE) for a given region assume two homogeneous premises, the contact mechanisms and diffusion rates, disregarding heterogeneous factors as different contact rates for each municipality and the flow of contaminated people among them. This work considers a hybrid model for covid-19, based on local SIR models and the population flow network among municipalities, responsible for a complex lag dynamic in their contagion curves. Based on actual infection data, local contact rates ( β ) are evaluated. The epidemic evolution at each municipality depends on the local SIR parameters and on the inter-municipality transport flow. When heterogeneity of β values and flow network are included, forecasts differ from those of the homogeneous ODE model. This effect is more relevant when more municipalities are considered, hinting that the latter overestimates new cases. In addition, mitigation scenarios are assessed to evaluate the effect of earlier interventions reducing the inter-municipality flux. Restricting the flow between municipalities in the initial stage of the epidemic is fundamental for flattening the contamination curve, highlighting advantages of a contamination lag between the capital curve and those of other municipalities in the territories., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Elsevier B.V. All rights reserved.)

Urgent treatments, in any modality, to fight SARS-CoV-2 infections are desired by society in general, by health professionals, by Estate-leaders and, mainly, by the scientific community, because one thing is certain amidst the numerous uncertainties regarding COVID-19: knowledge is the means to discover or to produce an effective treatment against this global disease. Scientists from several areas in the world are still committed to this mission, as shown by the accelerated scientific production in the first half of 2020 with over 25,000 published articles related to the new coronavirus. Three great lines of publications related to COVID-19 were identified for building this article: The first refers to knowledge production concerning the virus and pathophysiology of COVID-19; the second regards efforts to produce vaccines against SARS-CoV-2 at a speed without precedent in the history of science; the third comprehends the attempts to find a marketed drug that can be used to treat COVID-19 by drug repurposing. In this review, the drugs that have been repurposed so far are grouped according to their chemical class. Their structures will be presented to provide better understanding of their structural similarities and possible correlations with mechanisms of actions. This can help identifying anti-SARS-CoV-2 promising therapeutic agents., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The occurrence of superconductivity in doped SrTiO 3 at low carrier densities points to the presence of an unusually strong pairing interaction that has eluded understanding for several decades. We report experimental results showing the pressure dependence of the superconducting transition temperature, T c , near to optimal doping that sheds light on the nature of this interaction. We find that T c increases dramatically when the energy gap of the ferroelectric critical modes is suppressed, i.e., as the ferroelectric quantum critical point is approached in a way reminiscent to behaviour observed in magnetic counterparts. However, in contrast to the latter, the coupling of the carriers to the critical modes in ferroelectrics is predicted to be small. We present a quantitative model involving the dynamical screening of the Coulomb interaction and show that an enhancement of T c near to a ferroelectric quantum critical point can arise due to the virtual exchange of longitudinal hybrid-polar-modes, even in the absence of a strong coupling to the transverse critical modes.

Background and study aims  Esophageal squamous cell carcinoma (ESCC) is the most common secondary tumor in patients with head and neck squamous cell cancer (HNSCC). Currently, endoscopic submucosal dissection (ESD) is the preferred approach to manage superficial ESCC, however, it remains to be elucidated whether patients with HNSCC and early ESCC managed by ESD have different outcomes. Patients and methods  We retrospectively analyzed esophageal ESD for early ESCC from September 2009 to September 2017 and the following variables: demographics, tumor and specimen size, Paris classification, location, en bloc and R0 resection rates, overall survival (OS) and adverse events (AEs). To reduce selection bias, propensity score matching was applied to compare the results. Results  Eighty-nine ESDs were performed in 81 consecutive patients (47 with HNSCC and 34 without HNSCC). Patients with HNSCC who developed superficial ESCC were found to be younger and to refer a more frequent history of alcohol ingestion and smoking. There was no difference in lesion size, number of lesions, procedure time, en bloc resection rate, R0 resection rate, local recurrence and adverse event rate between the two groups. The histological depth of invasion for patients with HNSCC was significantly shallower before ( P  = 0.016) and after ( P  = 0.047) matching. The overall survival rate was similar in both groups. Conclusions  Patients with HNSCC have earlier detection of ESCC, probably due to endoscopic screening. Previous history of chemoradiation and surgery for HNSCC does not affect procedure time, AEs and OS., Competing Interests: Competing interests The authors declare that they have no conflict of interest.

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 μg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 μg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: None

Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC 50 values between 53.23 and 357.97 μM. Concerning the evaluation against L. amazonensis promastigote forms, IC 50 values ranged between 12.31 and  > 481.52 μM, while the activity against L. infantum promastigotes obtained IC 50 values between 4.36 and 23.35 μM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC 50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 10 6 and 1.43 × 10 5 , respectively, and DNA binding mode by intercalation. The IC 50 values were obtained between 0.81 and 1.48 μM and topoisomerase inhibition results in 10 μM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The present work aimed to carry out in vitro biological assays of indol-3-yl derivatives thiosemicarbazones (2a-e) and 4-thiazolidinones (3a-d) against juvenile and adult worms of S. mansoni, as well as the in silico determination of pharmacokinetic parameters for the prediction of the oral bioavailability of these derivatives. All compounds were initially screened at a concentration of 200 μM against S. mansoni adult worms and the results evidenced the good activity of compounds 2b, 2d and 3b, which caused 100% mortality after 24, 48 and 72 h, respectively. Subsequent studies with these same compounds revealed that compound 2b was able to reduce the viability of the parasites by 85% and 83% at concentrations of 200 and 100 μM, respectively. In relation to the juvenile worms, all compounds (2b, 2d and 3b) were able to cause mortality, but compound 2b demonstrated better activity causing 100% mortality in 48 h. Additionally, it was possible to observe reduction in the viability of juvenile worms of 85%, 81% and 64% at concentrations of 200, 100 and 50 μM, respectively. Several ultrastructural damages were observed when adult and juvenile S. mansoni worms were exposed to compound 2b (200 μM) that was characterized by extensive destruction by the integument, which may justify the mortality rate of cultured parasites. In the DNA interaction assay, fragmentation of the genetic material of adult worms when treated with compound 2b (200 μM) was evidenced, indicating the apoptosis process as mechanism of parasite death. Regarding pharmacokinetic properties, all derivatives are according to the required parameters, predicting good oral bioavailability for the studied compounds. The results presented in this study reveal the good activity of compound 2b in both adult and juvenile worms of S. mansoni, pointing this compound as promising in the development of further studies on schistosomicidal activity., (Copyright © 2019. Published by Elsevier B.V.)

In the present study, acridine-thiosemicarbazones (ATD) derivatives were tested for their interaction properties with BSA through UV-Vis absorption and fluorescence spectroscopic studies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated after the derivatives were added to the BSA. Values for the binding constant (K b ) ranged from 1.62 × 10 4 to 8.71 × 10 5  M -1 and quenching constant (K SV ) from 3.46 × 10 2 to 7.83 × 10 3  M -1 indicating a good affinity to BSA protein. Complementary, two compounds were selected to assess their inhibition activity against topoisomerase IIα enzyme, of which derivative 3a presented the best result. Moreover, to evaluate protein-ligand interactions, as well as the antitopoisomerase potential of these compounds, tests of molecular modeling were performed between all compounds using the albumin and Topoisomerase IIα/DNA complex. Finally, in silico studies showed that all derivatives used in this research displayed good oral bioavailability potential., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the Staphylococcus aureus 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the in silico study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC > 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent in vitro inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of -9.03 Kcal/mol and -9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against S. aureus SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells., (Copyright © 2019 Elsevier Ltd. All rights reserved.)