Blockade of Attachment and Fusion Receptors Inhibits HIV-1 Infection of Human Cervical Tissue

Identification of cellular factors involved in HIV-1 entry and transmission at mucosal surfaces is critical for understanding viral pathogenesis and development of effective prevention strategies. Here we describe the evaluation of HIV-1 entry inhibitors for their ability to prevent infection of, and dissemination from, human cervical tissue ex vivo. Blockade of CD4 alone or CCR5 and CXCR4 together inhibited localized mucosal infection. However, simultaneous blockade of CD4 and mannose-binding C-type lectin receptors including dendritic cell–specific intercellular adhesion molecule–grabbing integrin was required to inhibit HIV-1 uptake and dissemination by migratory cells. In contrast, direct targeting of HIV-1 by neutralizing mAb b12 and CD4-IgG2 (PRO-542) blocked both localized infection and viral dissemination pathways. Flow cytometric analysis and immunostaining of migratory cells revealed two major populations, CD3+HLA-DR− and CD3−HLA-DR+ cells, with a significant proportion of the latter also expressing dendritic cell–specific intercellular adhesion molecule–grabbing integrin. Bead depletion studies demonstrated that such HLA-DR+ cells accounted for as much as 90% of HIV-1 dissemination. Additional studies using immature monocyte-derived dendritic cells demonstrated that although mannose-binding C-type lectin receptors and CD4 are the principal receptors for gp120, other mechanisms may account for virus capture. Our identification of the predominant receptors involved in HIV-1 infection and dissemination within human cervical tissue highlight important targets for microbicide development

Is the treatment with biological or non-biological DMARDS a modifier of periodontal condition in patients with rheumatoid arthritis?

Background and objective: Experimental models suggest the use of different therapy protocols in rheumatoid arthritis (RA) as modulators on periodontal condition. This study evaluated the effects of conventional drug treatment and anti-TNF therapy in patients with RA on microbiological and periodontal condition, establishing the association of markers of periodontal infection with indexes of rheumatic activity. Materials and methods: One hundred seventy nine individuals with RA were evaluated (62 with anti-TNF-. and 115 with only DMARDs). The periodontal evaluation included plaque and gingival indexes, bleeding on probing (BOP), clinical attachment loss (CAL), pocket depth (PD) and subgingival plaque samples for microbiological analysis. Rheumatologic evaluations included a clinical examination, rheumatoid factor (RF), antibodies against cyclic-citrullinated peptides (ACPAs), and activity markers (DAS28-ERS), high sensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR). Results: Anti-TNF-alpha therapy influenced periodontal microbiota with a higher frequency of T. denticola (p=0.01). Methotrexate combined with leflunomide exhibited a higher extension of CAL (p=0.005), and anti-TNF-alpha therapy with methotrexate was associated with a lower extension of CAL (p=0.05). The use of corticosteroids exerted a protective effect on the number of teeth (p=0.027). The type of DMARD affected P. gingivalis, T. forsythia and E. nodatum presence. Elevated ACPAs titers were associated with the presence of red complex periodontal pathogens (p=0.025). Bleeding on probing was associated with elevated CPR levels (p=0.05), and ESR was associated with a greater PD (p=0.044) and presence of red complex (p=0.030). Conclusion: Different pharmacological treatments for RA affect the clinical condition and subgingival microbiota

Evaluation of commercial myxomatosis vaccines against recombinant myxoma virus (ha-MYXV) in Iberian hare and wild rabbit

Research Areas: Immunology ; Research & Experimental MedicineThe recent emergence of a new myxoma virus capable of causing disease in the Iberian hare (Lepus granatensis) has resulted in numerous outbreaks with high mortality leading to the reduction, or even the disappearance, of many local populations of this wild species in the Iberian Peninsula. Currently, the available vaccines that prevent myxomatosis in domestic rabbits caused by classic strains of myxoma virus have not been assessed for use in Iberian hares. The main objective of this study was to evaluate the efficacy of commercial rabbit vaccines in Iberian hares and wild rabbits against the natural recombinant myxoma virus (ha-MYXV), bearing in mind its application in specific scenarios where capture is possible, such as genetic reserves. The study used a limited number of animals (pilot study), 15 Iberian hares and 10 wild rabbits. Hares were vaccinated with Mixohipra-FSA vaccine (Hipra) and Mixohipra-H vaccine (Hipra) using two different doses, and rabbits were vaccinated with the Mixohipra-H vaccine or the Nobivac Myxo-RHD PLUS (MSD Animal Health) using the recommended doses for domestic rabbits. After the vaccination trials, the animals were challenged with a wild type strain of ha-MYXV. The results showed that no protection to ha-MYXV challenge was afforded when a commercial dose of Mixohipra-FSA or Mixohipra-H vaccine was used in hares. However, the application of a higher dose of Mixohipra-FSA vaccine may induce protection and could possibly be used to counteract the accelerated decrease of wild hare populations due to ha-MYXV emergence. The two commercial vaccines (Mixohipra-H and Nobivac Myxo-RHD PLUS) tested in wild rabbits were fully protective against ha-MYXV infection. This knowledge gives more insights into ha-MYXV management in hares and rabbits and emphasises the importance of developing a vaccine capable of protecting wild populations of Iberian hare and wild rabbit towards MYXV and ha-MYXV strainsinfo:eu-repo/semantics/publishedVersio

An approach to uncover the relationship between 17b-estradiol and ESR1/ESR2 ratio in the regulation of canine corpus luteum

The canine corpus luteum (CL) is able to synthetise, activate and deactivate 17b-estradiol (E2) and also expresses nuclear estrogen receptors in a time-dependent manner during diestrus. Nevertheless, we are still missing a better comprehension of E2 functions in the canine CL, especially regarding the specific roles of estrogen receptor alpha (ERa) and ERb, encoded by ESR1 and 2, respectively. For that purpose, we analyzed transcriptomic data of canine non-pregnant CL collected on days 10, 20, 30, 40, 50 and 60 of diestrus and searched for differentially expressed genes (DEG) containing predicted transcription factor binding sites (TFBS) for ESR1 or ESR2. Based on biological functions of DEG presenting TFBS, expression of select transcripts and corresponding proteins was assessed. Additionally, luteal cells were collected across specific time points during diestrus and specificity of E2 responses was tested using ERa and/or ERb inhibitors. Bioinformatic analyses revealed 517 DEGs containing TFBS, from which 67 for both receptors. In general, abundance of predicted ESR1 targets was greater in the beginning, while abundance of ESR2 targets was greater in the end of diestrus. ESR1/ESR2 ratio shifted from an increasing to a decreasing pattern from day 30 to 40 post ovulation. Specific receptor inhibition suggested an ERa-mediated positive regulation of CL function at the beginning of diestrus and an ERb-mediated effect contributing to luteal regression. In conclusion, our data points toward a broad spectrum of action of E2 and its nuclear receptors, which can also act as transcription factors for other genes regulating canine CL function

One-Year Changes in Urinary Microbial Phenolic Metabolites and the Risk of Type 2 Diabetes—A Case-Control Study

The intake of polyphenols has been associated with a risk reduction of type 2 diabetes. Nevertheless, to the best of our knowledge, the molecules that might be metabolically active after ingestion are only starting to be investigated regarding this metabolic disease. To investigate the association between one-year changes in urinary microbial phenolic metabolites (MPM) and the incidence of type 2 diabetes, we performed a case-control study using data and samples of the PREDIMED trial including 46 incident type 2 diabetes cases of 172 randomly selected participants. Eight urinary MPMs were quantified in urine by liquid chromatography coupled to mass spectrometry and used to assess their associations with type 2 diabetes risk by multivariable logistic regression models. Compared to participants in the lowest tertile of one-year changes in hydroxybenzoic acid glucuronide, those in the highest tertile had a significantly lowered probability of developing type 2 diabetes (OR [95% CI], 0.39 [0.23–0.64]; p < 0.001 for trend). However, when additionally adjusting for fasting plasma glucose, the statistical significance was lost. Changes in the dietary pattern can increase the concentrations of this compound, derived from many (poly)phenol-rich foods, and might be changing the gut microbial population as well, promoting the production of the metabolite.This research was funded by CICYT [AGL2016-75329-R] PID2020-114022RB-I00, CIBEROBN Instituto de Salud Carlos III, ISCIII from the Ministerio de Ciencia, Innovación y Universidades, (AEI/FEDER 10.13039/501100011033, UE), and Generalitat de Catalunya (GC) [2017SGR196]. M.M.-M. is supported by the FPU17/00513 grant. I.D.-L. thanks the Spanish Ministry of Science Innovation and Universities for the Formación de Profesorado Universitario (FPU20/02478) contract. E.P.L.-S. is supported by the FI-SDUR (EM/3345/2020) grant from the Generalitat de Catalunya. I.P.-M. is supported by the FI-SDUR (EMC/2703/2019). Partial funding for open access charge: Universidad de Málaga

FAD-Linked Autofluorescence and Chemically-Evoked Zinc Changes at Hippocampal Mossy Fiber-CA3 Synapses

Glutamatergic vesicles in hippocampal mossy fiber presynaptic boutons release zinc, which plays a modulatory role in synaptic activity and LTP. In this work, a fluorescence microscopy technique and the fluorescent probe for cytosolic zinc, Newport Green (NG), were applied, in a combined study of autofluorescence and zinc changes at the hippocampal mossy fiber-CA3 synaptic system. In particular, the dynamics of flavoprotein (FAD) autofluorescence signals, was compared to that of postsynaptic zinc signals, elicited both by high K+ (20 mM) and by tetraethylammonium (TEA, 25 mM). The real zinc signals were obtained subtracting autofluorescence values, from corresponding total NG-fluorescence data. Both autofluorescence and zinc-related fluorescence were raised by high K+. In contrast, the same signals were reduced during TEA exposure. It is suggested that the initial outburst of TEA-evoked zinc release might activate ATP-sensitive K+ (KATP) channels, as part of a safeguard mechanism against excessive glutamatergic action. This would cause sustained inhibition of zinc signals and a more reduced mitochondrial state. In favor of the “KATP channel hypothesis”, the KATP channel blocker tolbutamide (250 μM) nearly suppressed the TEA-evoked fluorescence changes. It is concluded that recording autofluorescence from brain slices is essential for the accurate assessment of zinc signals and actions

Mercury exposure, malaria, and serum antinuclear/antinucleolar antibodies in amazon populations in Brazil: a cross-sectional study

BACKGROUND: Mercury is an immunotoxic metal that induces autoimmune disease in rodents. Highly susceptible mouse strains such as SJL/N, A.SW, B10.S (H-2(s)) develop multiple autoimmune manifestations after exposure to inorganic mercury, including lymphoproliferation, elevated levels of autoantibodies, overproduction of IgG and IgE, and circulating immune complexes in kidney and vasculature. A few studies have examined relationships between mercury exposures and adverse immunological reactions in humans, but there is little evidence of mercury-associated autoimmunity in humans. METHODS: To test the immunotoxic effects of mercury in humans, we studied communities in Amazonian Brazil with well-characterized exposures to mercury. Information was collected on diet, mercury exposures, demographic data, and medical history. Antinuclear and antinucleolar autoantibodies (ANA and ANoA) were measured by indirect immunofluorescence. Anti-fibrillarin autoantibodies (AFA) were measured by immunoblotting. RESULTS: In a gold mining site, there was a high prevalence of ANA and ANoA: 40.8% with detectable ANoA at ≥1:10 serum dilution, and 54.1% with detectable ANA (of which 15% had also detectable ANoA). In a riverine town, where the population is exposed to methylmercury by fish consumption, both prevalence and levels of autoantibodies were lower: 18% with detectable ANoA and 10.7% with detectable ANA. In a reference site with lower mercury exposures, both prevalence and levels of autoantibodies were much lower: only 2.0% detectable ANoA, and only 7.1% with detectable ANA. In the gold mining population, we also examined serum for AFA in those subjects with detectable ANoA (≥1:10). There was no evidence for mercury induction of this autoantibody. CONCLUSIONS: This is the first study to report immunologic changes, indicative of autoimmune dysfunction in persons exposed to mercury, which may also reflect interactions with infectious disease and other factors

Representations of Portugal in Herman Hesse, Philip Roth and Paul Auster

The aim of my research is to answer the question: How is Portugal seen by non-Portuguese fictionists? The main reason why I chose this research line is the following: Portuguese essayists like Eduardo Lourenço and José Gil (2005) focus their attention on the image or representation of Portugal as conceived by the Portuguese; indeed there is a tendency in Portuguese cultural studies (and, to a certain extent, also in Portuguese philosophical studies) to focus on studying the so-called ‗portugalidade‘ (portugueseness), i.e., the essence of being Portuguese. In my view, the problem with the studies I have been referring to is that everything is self-referential, and if ‗portugueseness‘ is an issue, then it might be useful, when dealing with it, to separate subject from object of observation. That is the reason why we, in the CEI (Centro de Estudos Interculturais), decided to start this research line, which is an inversion in the current tendency of the studies about ‗portugueseness‘: instead of studying the image or representation of Portugal by the Portuguese, my task is to study the image or representation of Portugal by the non-Portuguese, in this case, in non-Portuguese fiction. For the present paper I selected three writers of the 20th century: the German Hermann Hesse and the North-Americans Philip Roth and Paul AusterO propósito da minha pesquisa é responder à questão: como é Portugal visto pelos escritores de ficção estrangeiros? A principal razão pela qual escolhi esta linha de investigação é o seguinte: ensaístas portugueses, como Eduardo Lourenço e José Gil (2005), centram a sua atenção na imagem ou na representação de Portugal tal como é concebida pelos próprios portugueses. De facto, existe uma tendência nos estudos culturais portugueses (e também, até certo ponto, nos estudos filosóficos) para se centrarem na chamada ‗portugalidade‘, ou seja, na essência de ser português. No meu ponto de vista, o problema com os estudos que referi anteriormente é que tudo é auto-referencial. E se a ‗portugalidade‘ é uma questão a ter em conta, então pode ser útil, ao estudá-la, separarmos o sujeito do objecto de observação. É esta a razão pela qual nós, no CEI (Centro de Estudos Interculturais), decidimos começar esta linha de investigação, que é uma inversão da tendência corrente dos estudos sobre a ‗portugalidade‘: ao invés de estudar a imagem ou a representação de Portugal pelos portugueses, a minha tarefa é estudar a imagem ou a representação de Portugal pelos não-portugueses, neste caso, na ficção não-portuguesa. Para este artigo seleccionei três escritores do século XX: o alemão Hermann Hesse e os norte-americanos Philip Roth e Paul Auster

description of the methodological approach

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