New Peptide Functionalized Nanostructured Lipid Carriers with CNS Drugs and Evaluation Anti-proliferative Activity

Nanoparticulate systems have been widely investigated as delivery vectors for efficient drug delivery in different diseases. Nanostructured lipid carriers (NLC) are composed of both solid and liquid lipids (glyceryl dibehenate and diethylene glycol monoethyl ether) and have demonstrated enhanced biological compatibility and increased drug loading capability. Furthermore, the use of peptides, in particular cell-penetrating peptides, to functionalize nanoparticles and enhance cell membrane permeation was explored in this paper. In this paper, we described the synthesis of a new conjugated of tranylcypromine with MAP. In addition, taking into consideration our previous results, this study developed different NLCs loaded with three central nervous system (CNS) drugs (tacrine (TAC), rasagiline (RAS), and tranylcypromine (TCP)) functionalized with model amphipathic peptide (MAP) and evaluated their activity against cancer cells. Particle size analysis demonstrated NLC presented less than 200 nm and a polydispersity index less than 0.3. Moreover, in vitro results showed that conjugation of MAP with drugs led to a higher decrease in cell viability of a neuroblastoma cell line and Caco-2 cell line, more than MAP alone. Furthermore, NLC encapsulation contributed to higher cellular delivery and enhanced toxic activity at lower concentrations when compared with free or co-administration drug-MAP conjugate.Funding: This work was financed by FEDER—Fundo Europeu de Desenvolimento Regional through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia, in a framework of the projects in CINTESIS, R&D Unit (reference UIDB/4255/2020, RISE (RISELA/P/0053/2020) and iMed.ULisboa (UID/DTP/04138/2019), as well by LA/P/0045/2020 (ALiCE), UIDB/50020/2020 and UIDP/50020/2020 (LSRE-LCM), funded by national funds through FCT/MCTES (PIDDAC). N.V. also thanks support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004 and CHAIR in Onco-Innovation. Acknowledgments: N.V. thanks support FCT and FEDER (European Union), award number IF/00092/ 2014/CP1255/CT0004 and CHAIR in Onco-Innovation. S.S. thanks FCT for PhD Grant (PD/BD/135456/ 2017) and PhD Programme in Medicines and Pharmaceutical Innovation (i3DU) from the University of Lisbon (Portugal) and the University of Porto (Portugal). D.D. acknowledges FCT for funding her PhD grant (SFRH/BD/140734/2018).info:eu-repo/semantics/publishedVersio

Chaos in Anisotropic Pre-Inflationary Universes

We study the dynamics of anisotropic Bianchi type-IX models with matter and cosmological constant. The models can be thought as describing the role of anisotropy in the early stages of inflation. The concurrence of the cosmological constant and anisotropy are sufficient to produce a chaotic dynamics in the gravitational degrees of freedom, connected to the presence of a critical point of saddle-center type in the phase space of the system. The invariant character of chaos is guaranteed by the topology of the cylinders emanating from unstable periodic orbits in the neighborhood of the saddle-center. We discuss a possible mechanism for amplification of specific wavelengths of inhomogeneous fluctuations in the models. A geometrical interpretation is given for Wald's inequality in terms of invariant tori and their destruction by increasing values of the cosmological constant.Comment: 14 pages, figures available under request. submitted to Physical Review

Homoclinic chaos in the dynamics of a general Bianchi IX model

The dynamics of a general Bianchi IX model with three scale factors is examined. The matter content of the model is assumed to be comoving dust plus a positive cosmological constant. The model presents a critical point of saddle-center-center type in the finite region of phase space. This critical point engenders in the phase space dynamics the topology of stable and unstable four dimensional tubes $R \times S^3$, where $R$ is a saddle direction and $S^3$ is the manifold of unstable periodic orbits in the center-center sector. A general characteristic of the dynamical flow is an oscillatory mode about orbits of an invariant plane of the dynamics which contains the critical point and a Friedmann-Robertson-Walker (FRW) singularity. We show that a pair of tubes (one stable, one unstable) emerging from the neighborhood of the critical point towards the FRW singularity have homoclinic transversal crossings. The homoclinic intersection manifold has topology $R \times S^2$ and is constituted of homoclinic orbits which are bi-asymptotic to the $S^3$ center-center manifold. This is an invariant signature of chaos in the model, and produces chaotic sets in phase space. The model also presents an asymptotic DeSitter attractor at infinity and initial conditions sets are shown to have fractal basin boundaries connected to the escape into the DeSitter configuration (escape into inflation), characterizing the critical point as a chaotic scatterer.Comment: 11 pages, 6 ps figures. Accepted for publication in Phys. Rev.

Jaboticaba (Myrciaria jaboticaba) powder consumption improves the metabolic profile and regulates gut microbiome composition in high-fat diet-fed mice

The consumption of a high-fat diet can cause metabolic syndrome and induces host gut microbial dysbiosis and non-alcoholic fatty liver disease (NAFLD). We evaluated the effect of polyphenol-rich jaboticaba peel and seed powder (JPSP) on the gut microbial community composition and liver health in a mouse model of NAFLD. Three-month-old C57BL/6 J male mice, received either a control (C, 10% of lipids as energy, n = 16) or high-fat (HF, 50% of lipids as energy, n = 64) diet for nine weeks. The HF mice were randomly subdivided into four groups (n = 16 in each group), three of which (HF-J5, HF-J10, and HF-J15) were supplemented with dietary JPSP for four weeks (5%, 10%, and 15%, respectively). In addition to attenuating weight gain, JPSP consumption improved dyslipidemia and insulin resistance. In a dose-dependent manner, JPSP consumption ameliorated the expression of hepatic lipogenesis genes (AMPK, SREBP-1, HGMCoA, and ABCG8). The effects on the microbial community structure were determined in all JPSP-supplemented groups; however, the HF-J10 and HF-J15 diets led to a drastic depletion in the species of numerous bacterial families (Bifidobacteriaceae, Mogibacteriaceae, Christensenellaceae, Clostridiaceae, Dehalobacteriaceae, Peptococcaceae, Peptostreptococcaceae, and Ruminococcaceae) compared to the HF diet, some of which represented a reversal of increases associated with HF. The Lachnospiraceae and Enterobacteriaceae families and the Parabacteroides, Sutterella, Allobaculum, and Akkermansia genera were enriched more in the HF-J10 and HF-J15 groups than in the HF group. In conclusion, JPSP consumption improved obesity-related metabolic profiles and had a strong impact on the microbial community structure, thereby reversing NAFLD and decreasing its severity.This work was financially supported by Brazilian funding: FAPERJ – Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ: E-26/202.677/2018, E-26/010.002203/2019) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES) – Finance code 001. Benjamin Willing was supported by the Canada Research Chair Program and his laboratory received funding from the Canadian Natural Science and Engineering Research Council (NSERC

Sensitization to inhalant and food allergens in Brazilian atopic children by in vitro total and specific IgE assay: Allergy Project - PROAL

OBJECTIVE: To determine the frequency of sensitization to inhalant and food allergens in children seen at Brazilian allergy services. PATIENTS AND METHODS: Total and specific IgE serum levels to inhalant and food allergens (RAST, UniCAP® - Pharmacia) were measured in 457 children accompanied in pediatric allergy services and in 62 control children age matched. RAST equal or higher than class 1 was considered as positive (R+). RESULTS: Frequency of R+ was significantly higher among atopics (361/457, 79%) when compared to controls (16/62, 25.8%). There were no differences according to gender. The frequency of R+ to all allergens evaluated were higher among atopics when compared to controls. Significantly higher total IgE serum levels were observed among the atopics with R+ in comparison to those with R-. The frequency of R+ to main inhalant allergens were: D. pteronyssinus = 66.7% x 14.5% (p < 0.05), D. farinae = 64.5% x 17.8% (p < 0.05), B. tropicalis = 55.2% x 19.4% (p < 0.05), cockroach = 32.8% x 9.7% (p < 0.05), and cat = 12% x 8.1%. In relation to food allergens we observed: fish = 29.5% x 11.3% (p < 0.05), egg = 24.4% x 4.8% (p < 0.05), cow's milk = 23.1% x 3.2% (p < 0.05), wheat = 20% x 8.1% (p < 0.05), peanuts = 14% x 4.8% (p < 0.05), soy = 11.8% x 4.8% (p < 0.05), and corn = 10.6% x 4.8% (p < 0.05). With respect of age, food allergen sensitization predominates in young children whereas the inverse occurs with inhalant allergens. CONCLUSIONS: There was a predominant frequency of sensitization to inhalant allergens, mainly house dust mites in the evaluated patients. Food allergens were also responsible for a significant proportion of sensitization, mainly in infants.OBJETIVO: Determinar a freqüência de sensibilização a alérgenos inalantes e alimentares em crianças atendidas em serviços brasileiros de alergia. PACIENTES E MÉTODOS: IgE sérica total e específica (RAST) a alérgenos inalantes e alimentares (UniCAP® - Pharmacia) foram determinados em 457 crianças acompanhadas em serviços de alergia pediátrica e em um grupo de controles (n = 62). Resultados classe igual ou maior que 1 foram considerados positivos (R+). RESULTADOS: A freqüência de R+ foi significantemente maior entre os atópicos (361/457, 79%) quando comparados aos controles (16/62, 25,8%). Não houve diferenças quanto ao sexo. A prevalência de R+ entre os atópicos foi significantemente maior para todos os alérgenos avaliados. Os níveis séricos de IgE total foram significantemente mais elevados entre os atópicos com R+ quando comparados aos com R-. Comparando-se atópicos e controles, a freqüência de R+ para os principais alérgenos inalantes foi como segue: D. pteronyssinus = 66,7 versus 14,5% (p < 0,05), D. farinae = 64,5 versus 17,8% (p < 0,05), B. tropicalis = 55,2 versus 19,4% (p < 0,05), barata = 32,8 versus 9,7% (p < 0,05) e gato = 12 versus 8,1%. Com os alimentos, observou-se: peixe = 29,5 versus 11,3% (p < 0,05), ovo = 24,4 versus 4,8% (p < 0,05), leite de vaca = 23,1 versus 3,2% (p < 0,05), trigo = 20 versus 8,1% (p < 0,05), amendoim = 14 versus 4,8% (p < 0,05), soja = 11,8 versus 4,8% (p < 0,05) e milho = 10,6 versus 4,8% (p < 0,05). Segundo a idade, os R+ aos alimentares predominaram entre as crianças mais jovens, e o inverso ocorreu com os inalantes. CONCLUSÕES: Nesta população, predominou a sensibilização aos aeroalérgenos, sobretudo aos ácaros domiciliares, e os alimentos foram importantes em crianças mais jovens.Universidade Federal de São Paulo (UNIFESP) Departamento de Pediatria Disciplina de Alergia e Imunologia Clínica e ReumatologiaUniversidade Federal de São Paulo (UNIFESP)Grupo PROALUNIFESP, Depto. de Pediatria Disciplina de Alergia e Imunologia Clínica e ReumatologiaUNIFESPSciEL

BK virus-specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation

© 2020 by The American Society of HematologyClinical disease caused by BK virus reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Because of the lack of effective antiviral agents, BK virus-specific T cells are emerging as a potential therapy for BK virus disease, but the immune response to BK virus after allogeneic HCT has not been well characterized. Our study describes reconstitution of BK virus-specific T-cell immunity in 77 adult patients after HCT. All patients had urinary symptoms, and urine was tested for BK virus replication; 33 patients were positive for BK virus (cases), and 44 were negative (controls). In BK virus cases, the median time to first positive test was 75 days (range, 2-511). BK virus cases had lower CD4 T-cell counts 3 to 9 months after transplant, but CD8 T-cell counts were similar in cases and controls. BK virus-specific T cells were identified by cytokine flow cytometry in cryopreserved samples collected prospectively. BK virus-specific CD4 T cells producing T helper 1 (Th1) cytokines recovered quickly after HCT. BK virus-specific T cells were detected more frequently in patients with BK virus reactivation at most time points, and CD4 T cells producing Th1 cytokines were more frequent than BK virus-specific cytolytic CD8 T cells. Early detection of interferon-γ+ and cytolytic BK virus-specific CD4 T cells was associated with lower rates of hematuria among cases. Overall, our study describes recovery of BK virus-specific T cells after HCT and the distinct roles for BK virus-specific T cells in the development and resolution of clinical symptoms.This work was supported by a Collaborative Research Grant from the Harvard Medical School–Portugal Program in Translational Research HMSP-ICT/0001/201, National Institutes of Health, National Cancer Institute grants CA183559, CA183560, and CA229092, and the Pasquarello Tissue Bank in Hematologic Malignancies. E.E. is a PhD candidate at Universidade de Lisboa, and this work is submitted in partial fulfillment of the requirement for a PhD and was supported by a grant for medical fellows enrolled in a PhD program (Subsídios aos Internos Doutorandos–SINTD) from Fundação para a Ciência e Tecnologia, number SFRH/SINTD/135312/2017info:eu-repo/semantics/publishedVersio

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson