Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine.

BACKGROUND: Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine. METHODS: In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases. RESULTS: A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%). CONCLUSIONS: The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).

Cardiometabolic health in people with HIV: expert consensus review.

OBJECTIVES: To develop consensus data statements and clinical recommendations to provide guidance for improving cardiometabolic health outcomes in people with HIV based on the knowledge and experience of an international panel of experts. METHODS: A targeted literature review including 281 conference presentations, peer-reviewed articles, and background references on cardiometabolic health in adults with HIV published between January 2016 and April 2022 was conducted and used to develop draft consensus data statements. Using a modified Delphi method, an international panel of 16 experts convened in workshops and completed surveys to refine consensus data statements and generate clinical recommendations. RESULTS: Overall, 10 data statements, five data gaps and 14 clinical recommendations achieved consensus. In the data statements, the panel describes increased risk of cardiometabolic health concerns in people with HIV compared with the general population, known risk factors, and the potential impact of antiretroviral therapy. The panel also identified data gaps to inform future research in people with HIV. Finally, in the clinical recommendations, the panel emphasizes the need for a holistic approach to comprehensive care that includes regular assessment of cardiometabolic health, access to cardiometabolic health services, counselling on potential changes in weight after initiating or switching antiretroviral therapy and encouraging a healthy lifestyle to lower cardiometabolic health risk. CONCLUSIONS: On the basis of available data and expert consensus, an international panel developed clinical recommendations to address the increased risk of cardiometabolic disorders in people with HIV to ensure appropriate cardiometabolic health management for this population.

T cell-mediated Immune response and correlates of inflammation and their relationship with COVID-19 clinical severity: not an intuitive guess.

BACKGROUND: Predictors of the outcome of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remain to be fully determined. We evaluated selected viral characteristics and immunological responses that might predict and/or correlate to the clinical outcome of COVID-19. METHODS: For individuals developing divergent clinical outcomes, the magnitude and breadth of T cell-mediated responses were measured within 36 h of symptom onset. Peripheral Blood Mononuclear Cells (PBMCs) were subjected to in vitro stimulation with SARS-CoV-2-based peptides. In addition, SARS-CoV-2 sequences were generated by metagenome, and HLA typing was performed using Luminex technology. FINDINGS: CD4+ T cell activation was negatively correlated with SARS-CoV-2 basal viral load in patients with severe COVID-19 (p = 0·043). The overall cellular immune response, as inferred by the IFN-γ signal, was higher at baseline for patients who progressed to mild disease compared to patients who progressed to severe disease (p = 0·0044). Subjects with milder disease developed higher T cell responses for MHC class I and II-restricted peptides (p = 0·033). INTERPRETATION: Mounting specific cellular immune responses in the first days after symptom onset, as inferred by IFN-γ magnitude in the ELISPOT assay, may efficiently favor a positive outcome. In contrast, progression to severe COVID-19 was accompanied by stronger cellular immune responses, higher CD4 + T cell activation, and a higher number of in silico predicted high-affinity class I HLA alleles.

Gluten-free diet for pediatric patients with coeliac disease: A position paper from the ESPGHAN gastroenterology committee, special interest group in coeliac disease.

BACKGROUND AND OBJECTIVE: Coeliac disease is a chronic, immune-mediated disorder for which the only treatment consists of lifelong strict adherence to gluten-free diet (GFD). However, there is a lack of evidence-based guidelines on the GFD dietary management of coeliac disease. This position paper, led by the Special Interest Group in coeliac disease of the European Society of Pediatric, Gastroenterology Hepatology, and Nutrition, supported by the Nutrition Committee and the Allied Health Professionals Committee, aims to present evidence-based recommendations on the GFD as well as how to support dietary adherence. METHODS: A wide literature search was performed using the MeSH Terms: "diet, gluten free," "gluten-free diet," "diets, gluten-free," "gluten free diet," and "coeliac disease" in Pubmed until November 8th, 2022. RESULTS: The manuscript provides an overview of the definition of the GFD, regulations as basis to define the term "gluten-free," which foods are naturally gluten-free and gluten-containing. Moreover, it provides recommendations and educational tips and infographics on suitable food substitutes, the importance of reading food labels, risk of gluten cross-contact at home and in public settings, nutritional considerations as well as factors associated to dietary adherence based on available evidence, or otherwise clinical expertise. CONCLUSIONS: This position paper provides guidance and recommendations to support children with coeliac disease to safely adhere to a GFD.

A Past Genetic Bottleneck from Argentine Beans and a Selective Sweep Led to the Race Chile of the Common Bean (Phaseolus vulgaris L.).

The domestication process of the common bean gave rise to six different races which come from the two ancestral genetic pools, the Mesoamerican (Durango, Jalisco, and Mesoamerica races) and the Andean (New Granada, Peru, and Chile races). In this study, a collection of 281 common bean landraces from Chile was analyzed using a 12K-SNP microarray. Additionally, 401 accessions representing the rest of the five common bean races were analyzed. A total of 2543 SNPs allowed us to differentiate a genetic group of 165 accessions that corresponds to the race Chile, 90 of which were classified as pure accessions, such as the bean types 'Tórtola', 'Sapito', 'Coscorrón', and 'Frutilla'. Our genetic analysis indicates that the race Chile has a close relationship with accessions from Argentina, suggesting that nomadic ancestral peoples introduced the bean seed to Chile. Previous archaeological and genetic studies support this hypothesis. Additionally, the low genetic diversity (π = 0.053; uHe = 0.53) and the negative value of Tajima' D (D = -1.371) indicate that the race Chile suffered a bottleneck and a selective sweep after its introduction, supporting the hypothesis that a small group of Argentine bean genotypes led to the race Chile. A total of 235 genes were identified within haplotype blocks detected exclusively in the race Chile, most of them involved in signal transduction, supporting the hypothesis that intracellular signaling pathways play a fundamental role in the adaptation of organisms to changes in the environment. To date, our findings are the most complete investigation associated with the origin of the race Chile of common bean.

Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor. METHODS: In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort. RESULTS: A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure. CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.).

Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries.

BACKGROUND: Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area. METHODS: We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries. RESULTS: We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR+ immature neuroblasts in the SVZ. In accordance, the inhibition of the TGF-α receptor, EGFR promotes migration of neuroblasts toward the injury leading to an elevated number of neuroblasts within the perilesional area. CONCLUSIONS: Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.

Dolutegravir-associated resistance mutations after first-line treatment failure in Brazil.

BACKGROUND: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. METHODS: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018. RESULTS: One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. CONCLUSIONS: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.

[Evaluation of a change in the serological diagnostic algorithm for Chagas disease in ColombiaAvaliação da mudança do algoritmo de diagnóstico sorológico da doença de Chagas na Colômbia]. / Evaluación del cambio del algoritmo de diagnóstico serológico para la enfermedad de Chagas en Colombia.

Objective: To evaluate the effects of changing the algorithm for serological diagnosis of T. cruzi infection in departmental-level public health laboratories and in the National Reference Laboratory of Colombia, from the perspective of access to diagnosis. Methods: A descriptive, cross-sectional study was carried out, based on secondary sources between 2015 and 2021, consolidating the number of serological tests carried out by the laboratories. A survey was developed to identify benefits and limitations in the implementation of the new algorithm for serological diagnosis. Totals, proportions, and averages of the number of tests were estimated by comparing two different periods. Results: Information from 33 public health laboratories was analyzed, 87.9% of which processed serological assays during the period under study. The use of serological tests increased after the publication of the new guideline in 2017, and the capacity to perform the second test increased from four to 33 public health laboratories. In absolute terms, ELISAs for antigens and recombinant antigens became the most performed tests in Colombia after 2017. Conclusions: The change in the algorithm for serological diagnosis of Chagas disease in Colombia in 2017 had positive effects on access to diagnosis since it facilitated the use of the second test. This change resulted in increased diagnostic coverage. The country's laboratories have access to a simple, timely, quality algorithm that could be implemented in almost any clinical laboratory in the country.

Objetivo: Avaliar os efeitos da mudança do algoritmo de diagnóstico sorológico da infecção por T. cruzi nos Laboratórios Departamentais de Saúde Pública e no Laboratório Nacional de Referência da Colômbia desde a perspectiva do acesso ao diagnóstico. Métodos: Foi realizado um estudo descritivo transversal a partir de fontes secundárias do período entre 2015 e 2021, consolidando-se o número de testes sorológicos realizados pelos laboratórios. Foi desenvolvido um questionário para identificar benefícios e limitações na implementação do novo algoritmo de diagnóstico sorológico. Os totais, as proporções e as médias do número de testes foram estimados pela comparação de dois períodos diferentes. Resultados: Dados de 33 laboratórios de saúde pública foram analisados, e constatou-se que 87,9% processaram testes sorológicos durante o período analisado. O uso de testes sorológicos aumentou após a publicação das novas diretrizes em 2017, e a capacidade de realizar um segundo teste aumentou de 4 para 33 laboratórios de saúde pública. O ELISA com antígeno total e o ELISA com antígeno recombinante se consolidaram como os testes mais realizados na Colômbia após 2017. Conclusões: A mudança no algoritmo de diagnóstico sorológico da doença de Chagas na Colômbia em 2017 teve efeitos positivos no acesso ao diagnóstico, facilitando o uso do segundo teste, o que resultou em maior cobertura diagnóstica. Os laboratórios do país têm à sua disposição um algoritmo simples, oportuno e de alta qualidade que poderia ser implementado em quase todos os laboratórios clínicos do país.

Migratory Response of Cells in Neurogenic Niches to Neuronal Death: The Onset of Harmonic Repair?

Harmonic mechanisms orchestrate neurogenesis in the healthy brain within specific neurogenic niches, which generate neurons from neural stem cells as a homeostatic mechanism. These newly generated neurons integrate into existing neuronal circuits to participate in different brain tasks. Despite the mechanisms that protect the mammalian brain, this organ is susceptible to many different types of damage that result in the loss of neuronal tissue and therefore in alterations in the functionality of the affected regions. Nevertheless, the mammalian brain has developed mechanisms to respond to these injuries, potentiating its capacity to generate new neurons from neural stem cells and altering the homeostatic processes that occur in neurogenic niches. These alterations may lead to the generation of new neurons within the damaged brain regions. Notwithstanding, the activation of these repair mechanisms, regeneration of neuronal tissue within brain injuries does not naturally occur. In this review, we discuss how the different neurogenic niches respond to different types of brain injuries, focusing on the capacity of the progenitors generated in these niches to migrate to the injured regions and activate repair mechanisms. We conclude that the search for pharmacological drugs that stimulate the migration of newly generated neurons to brain injuries may result in the development of therapies to repair the damaged brain tissue.

Chlamydia trachomatis, Neisseria gonorrhoeae and human papillomavirus infections of lower genital tract of Indigenous women from Xingu Indigenous Park.

INTRODUCTION: Xingu Indigenous Park (XIP) currently protects 16 ethnic Indigenous groups and is located in the central area of Brazil. XIP is the first and the largest Indigenous land to be recognized in the country. Community access is limited and restricted for the non-Indigenous population, and the Indigenous women are constantly dealing with shortages of medical care. High-risk human papillomavirus (HR-HPV) is the most common cause of cervical cancer and is detected in 99% of cervical precancers. HPV infections may be associated with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoeae, which are also important causative agents of sexually transmitted infections and are responsible for the most frequent bacterial infections in the world. The present study evaluated the frequency and potential impact of Chlamydia trachomatis, Neisseria gonorrhoeae, and HR-HPV in the Indigenous women of XIP. METHODS: In this cross-sectional study, 992 cervical-vaginal samples were collected from Indigenous women, using a Cervex-Brush, and were immediately placed in a SurePath medium. All samples were submitted to the cobas® 4800 detection system for the identification of 14 different types of HR-HPV, and the multiplex Abbott RealTime CT/NG assay for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. RESULTS: HR-HPV was detected in 18.2% of women; 6% were positive for HPV16, 5% for HPV18, and 81% for other types of HR-HPV. Co-infections of HPV16 and other types was observed in 5% of women, and 3% had co-infections of HPV18 and other types. Moreover, 1.8% of women were positive for Chlamydia trachomatis, while Neisseria gonorrhoeae was not detected. In women with HR-HPV, 33% had Chlamydia trachomatis infections, 28% were positive for HR-HPV other than HPV16 or HPV18, and 5% had co-infections of HPV16 and the other types of HPV. Younger women were found to be more susceptible to HPV infections. CONCLUSION: The findings indicate a high frequency of HR-HPV and a considerable frequency of Chlamydia trachomatis in the Indigenous women of XIP. The detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and/or HR-HPV does not present evidence of a potential interrelationship for a combined pathogenic action in these women.

Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1.

In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).

Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial.

BACKGROUND: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. METHODS: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient's HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients' cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. RESULTS: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. CONCLUSIONS: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829 , posted November 11th, 2016).

Long-term taurine administration improves motor skills in a tubulinopathy rat model by decreasing oxidative stress and promoting myelination.

The taiep rat undergoes hypomyelination and progressive demyelination caused by an abnormal microtubule accumulation in oligodendrocytes, which elicits neuroinflammation and motor behavior dysfunction. Based on taurine antioxidant and proliferative actions, this work explored whether its sustained administration from the embryonic age to adulthood could prevent neuroinflammation, stimulate cell proliferation, promote myelination, and relieve motor impairment. Taurine (50 mg/L of drinking water = 50 ppm) was given to taiep pregnant rats on gestational day 15 and afterward to the male offspring until eight months of age. We measured the levels of nitric oxide (NO), malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), CXCL1, CXCR2 receptor, growth factors (BNDF and FGF2), cell proliferation, and myelin content over time. Integral motor behavior was also evaluated. Our results showed that taurine administration significantly decreased NO and MDA + 4-HDA levels, increased cell proliferation, and promoted myelination in an age- and brain region-dependent fashion compared with untreated taiep rats. Taurine effect on chemokines and growth factors was also variable. Taurine improved vestibular reflexes and limb muscular strength in perinatal rats and fine movements and immobility episodes in adult rats. These results show that chronic taurine administration partially alleviates the taiep neuropathology.

Host-virus interaction and viral evasion.

With each infectious pandemic or outbreak, the medical community feels the need to revisit basic concepts of immunology to understand and overcome the difficult times brought about by these infections. Regarding viruses, they have historically been responsible for many deaths, and such a peculiarity occurs because they are known to be obligate intracellular parasites that depend upon the host's cell machinery for their replication. Successful infection with the production of essential viral components requires constant viral evolution as a strategy to manipulate the cellular environment, including host internal factors, the host's nonspecific and adaptive immune responses to viruses, the metabolic and energetic state of the infected cell, and changes in the intracellular redox environment during the viral infection cycle. Based on this knowledge, it is fundamental to develop new therapeutic strategies for controlling viral dissemination, by means of antiviral therapies, vaccines, or antioxidants, or by targeting the inhibition or activation of cell signaling pathways or metabolic pathways that are altered during infection. The rapid recovery of altered cellular homeostasis during viral infection is still a major challenge. Here, we review the strategies by which viruses evade the host's immune response and potential tools used to develop more specific antiviral therapies to cure, control, or prevent viral diseases.

Serological and molecular epidemiology of the Dengue, Zika and Chikungunya viruses in a risk area in Brazil.

BACKGROUND: The co-circulation of types of arbovirus in areas where they are endemic increased the risk of outbreaks and limited the diagnostic methods available. Here, we analyze the epidemiological profile of DENV, CHIKV and ZIKV at the serological and molecular level in patients with suspected infection with these arboviruses in the city of Juazeiro do Norte, Ceará, Brazil. METHODS: In 2016, the Central Public Health Laboratory (LACEN) of Juazeiro do Norte received 182 plasma samples from patients who visited health facilities with symptoms compatible with arbovirus infection. The LACEN performed serological tests for detection of IgM/IgG to DENV and CHIKV. They then sent these samples to the Retrovirology Laboratory of the Federal University of São Paulo and Faculty of Medical of the ABC where molecular analyses to confirm the infection by DENV, ZIKV and CHIKV were performed. The prevalence of IgM/IgG antibodies and of infections confirmed by RT-qPCR were presented with 95% confidence interval. RESULTS: In serologic analysis, 125 samples were positive for antibodies against CHIKV and all were positive for antibodies against DENV. A higher prevalence of IgG against CHIKV (63.20% with 95% CI: 45.76-70.56) than against DENV (95.05% with 95% CI: 78.09-98.12) was observed. When the samples were submitted to analysis by RT-qPCR, we observed the following prevalence: mono-infection by ZIKV of 19.23% (95% CI: 14.29-34.82) patients, mono-infection by CHIKV of 3.84% (95% CI: 2.01-5.44) and co-infection with ZIKV and CHIKV of 1.09% (95% CI: 0.89-4.56). CONCLUSION: The serologic and molecular tests performed in this study were effective in analyzing the epidemiological profile of DENV, CHIKV and ZIKV in patients with suspected infection by these arboviruses in the city of Juazeiro do Norte, Ceará/Brazil.

Novel bacteriocins produced by Lactobacillus fermentum strains with bacteriostatic effects in milk against selected indicator microorganisms.

The aim of this work was to isolate and characterize bacteriocins produced by 2 Lactobacillus fermentum strains isolated from artisanal Mexican Cocido cheese. Fractions (F ≤3 kDa) obtained from cell-free supernatants of Lb. fermentum strains J23 and J32 were further fractionated by reversed-phase HPLC on a C18 column. Antimicrobial activities of F ≤3 kDa and bacteriocin-containing fractions (BCF), obtained from fractionation of F ≤3 kDa against 4 indicator microorganisms, were determined by the disk diffusion method and growth inhibition in milk. Subsequently, isolated BCF were analyzed by reversed-phase HPLC tandem mass spectrometry. Results showed that BCF presented antimicrobial activity against the 4 indicator microorganisms tested. For J23, one of the fractions (F3) presented the highest activity against Escherichia coli and was also inhibitory against Staphylococcus aureus, Listeria innocua, Salmonella Typhimurium, and Salmonella Choleraesuis. Similarly, fractions F3 and F4 produced by J32 presented antimicrobial activity against all indicator microorganisms. Furthermore, generation time and growth rate showed that F3 from J23 presented significantly higher antimicrobial activity against the 4 indicator microorganisms (2 gram-positive and 2 gram-negative) when inoculated in milk compared with F3 from J32. Interestingly, this fraction presented a broader antimicrobial spectrum in milk than nisin (control). Reversed-phase HPLC tandem mass spectrometry analysis revealed the presence of several peptides in BCF; however, F3 from J23 that was the most active fraction of all presented only 1 bacteriocin. The chemical characterization of this bacteriocin suggested that it was a novel peptide with 10 hydrophobic AA residues in its sequence and a molecular weight of 2,056 Da. This bacteriocin and its producing strain, J23, may find application as a biopreservative against these indicator microorganisms in dairy products.

Volatile and sensory evaluation of Mexican Fresco cheese as affected by specific wild Lactococcus lactis strains.

Lactococcus lactis is the lactic acid bacteria most frequently used for the production of cheese starter cultures, mainly because of their efficient production of aroma compounds. However, commercial cultures do not always produce the typical aroma notes of artisanal raw-milk cheeses. Thus, the objective of this study was to characterize the volatile compounds generated by wild L. lactis strains in Mexican Fresco cheese made with pasteurized milk. Four strains of wild L. lactis were evaluated for their aroma production in Mexican Fresco cheese using sensory and instrumental analysis. The aroma profiles were evaluated by descriptive sensory analysis. Volatiles were determined by solid-phase microextraction and gas chromatography-mass spectrometry. Principal component analysis was applied to interpret analytical and sensory data. Mexican Fresco cheese aroma was described as milkfat, yogurt, yeasty, barny, dirty socks, and Fresco cheese. Cheese with L. lactis strains R7 or B7 were most similar to commercial raw milk Fresco cheese in all aroma descriptors. Volatiles identified in all cheeses were esters, acids, alcohols, ketones, and aldehydes, but the main differences were found for total volatile relative abundance. Also, volatile concentrations (µg/g) in commercial raw milk Fresco cheese and cheeses made with L. lactis R7 or B7 were 4 methyl esters [C4 (4.15 vs. 5.47-13.74), C6 (0.12 vs. 1.53-15.34), C8 (1.06 vs. 0.32-6.65), and C10 (0.62 vs. 0.41-3.74)], 7 acids [C4 (1.92 vs. 0.30-9.29), C6-C10 (0.05-4.48 vs. 0.11-30.45), and C12 (0.13 vs. 0.28-0.30)], 2 alcohols [(3-methyl-1-butanol (3.48 vs. 3.4-13.13) and phenylethyl alcohol (0.10 vs. 0.63-2.04)], and 1 ketone (acetoin; 1.22 vs. 0.28-0.99). The first 3 principal components explained 78.2% of the total variation and clearly distinguished 3 main groups. Cheese made with L. lactis R7 was classified in the same group as key compounds associated with Fresco cheese aroma and show potential as a starter in Mexican Fresco cheese manufacture.

Poro de Tabasco cheese: Chemical composition and microbiological quality during its artisanal manufacturing process.

Poro de Tabasco cheese (PTC) is one of the most popular cheeses in southern Mexico. It has been made by traditional, nonstandardized artisanal techniques dating back more than 50 yr. These techniques result in the cheese having a heterogeneous chemical and microbiological composition and, consequently, distinct organoleptic characteristics. Scientific interest in artisanal cheese is growing because it represents a source of bacteria with potential health benefits. However, the quality of raw-milk cheeses often does not comply with official sanitary standards. The objective of the present study was to explore the chemical composition and microbiological quality of PTC and to describe its production process. Based on chemical composition, this cheese can be classified as a hard, full-fat, fresh cheese, with moisture on a fat-free basis and fat in dry matter ranging from 41 to 55% and from 49 to 57%, respectively. The chemical and microbiological composition of PTC varied among the evaluated dairies due to the lack of standardization in the production process. Microbial populations decreased during production, which may be associated with high acidity and high salt and low moisture contents, the presence of lactic acid bacteria or antimicrobial substances, and the drainage of whey. However, despite the absence of Escherichia coli, Salmonella spp., and Listeria monocytogenes in final cheeses for all dairies, Staphylococcus aureus and its toxins were found in some samples from one dairy. Therefore, heat treatment for milk and good manufacturing practices should be implemented throughout the entire production process to ensure a safe product.

Photoimmunotherapy Using Cationic and Anionic Photosensitizer-Antibody Conjugates against HIV Env-Expressing Cells.

Different therapeutic strategies have been investigated to target and eliminate HIV-1-infected cells by using armed antibodies specific to viral proteins, with varying degrees of success. Herein, we propose a new strategy by combining photodynamic therapy (PDT) with HIV Env-targeted immunotherapy, and refer to it as HIV photoimmunotherapy (PIT). A human anti-gp41 antibody (7B2) was conjugated to two photosensitizers (PSs) with different charges through different linking strategies; "Click" conjugation by using an azide-bearing porphyrin attached via a disulfide bridge linker with a drug-to-antibody ratio (DAR) of exactly 4, and "Lysine" conjugation by using phthalocyanine IRDye 700DX dye with average DARs of 2.1, 3.0 and 4.4. These photo-immunoconjugates (PICs) were compared via biochemical and immunological characterizations regarding the dosimetry, solubility, and cell targeting. Photo-induced cytotoxicity of the PICs were compared using assays for apoptosis, reactive oxygen species (ROS), photo-cytotoxicity, and confocal microscopy. Targeted phototoxicity seems to be primarily dependent on the binding of PS-antibody to the HIV antigen on the cell membrane, whilst being independent of the PS type. This is the first report of the application of PIT for HIV immunotherapy by killing HIV Env-expressing cells.